JP6330118B2 - Formulation of histone deacetylase inhibitor combined with bendamustine and its use - Google Patents

Description

  A pharmaceutical composition comprising a combination of a histone deacetylase (HDAC) inhibitor compound and bendamustine for the treatment of cancer has been described. Treatment methods using pharmaceutical compositions and dosing regimens are also described.

  The acetylation status of nucleosome histones plays an important role in the regulation of gene expression. Nucleosomal histone deacetylation is catalyzed by a group of enzymes known as histone deacetylases (HDACs), which have eleven known isoforms. Histone deacetylation leads to chromatin condensation that leads to transcriptional repression, while acetylation causes local relaxation within specific chromosomal regions, making it accessible to transcriptional machinery that promotes transcription.

  In tumor cells, selective inhibitors of the HDAC enzyme lead to histone hyperacetylation. This is a gene containing many tumor suppressors that alters the transcriptional regulation of a subset of genes involved in cell cycle control, cell division, and apoptosis. Furthermore, HDAC inhibitors have been reported to suppress tumor growth in vivo. Inhibition of tumor growth is associated with hyperacetylation of histones and tubulin and may involve many mechanisms.

  HDAC inhibitors inhibit the growth of cancer cells in vitro and in vivo. N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide (Compound 1) is a hydroxa used in the treatment of human cancer. It is a mate-based HDAC inhibitor.

  Pharmaceutical compositions, methods of treating cancer, dosing regimens, and combination therapies are disclosed. A method for treating or preventing a patient's cancer is provided herein, the method comprising administering to the patient a bendamustine and a histone deacetylase (HDAC) inhibitor.

  In some examples, the cancer is a carcinoma, tumor, neoplasm, lymphoma, melanoma, glioma, sarcoma and blastoma. In certain embodiments, the carcinoma is selected from the group consisting of: cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adrenocortical carcinoma, well-differentiated carcinoma, squamous carcinoma, serous carcinoma ), Small cell carcinoma, invasive squamous cell carcinoma, large cell carcinoma, pancreatic islet cell carcinoma, oat cell carcinoma, squamous cell carcinoma, undifferentiated cancer, rod shaped carcinoma, renal cell carcinoma, papillary serous adenocarcinoma (papillary serous carcinoma) adenocarcinoma), Merkel cell carcinoma, hepatocellular carcinoma, soft tissue carcinoma, bronchial adenocarcinoma, capillary carcinoma (capillary carcinoma), bartholin adenocarcinoma, basal cell carcinoma, carcinosarcoma, papilloma / carcinoma, clear cell carcinoma, intimal gland Cancer, metastatic cancer of the mesothelioma, mucoepidermoid carcinoma, cholangiocarcinoma, actinic keratosis, cystadenoma, and hepatic adenoma.

  In certain other embodiments, the tumor is selected from the group consisting of: astrocytic tumor, malignant mesothelioma, ovarian germ cell tumor, supratent primitive ectodermal tumor, Wilms tumor, pituitary gland Tumor, extragonadal germ cell tumor, gastrinoma, germ cell tumor, gestational choriocarcinoma, brain tumor, pineal and supratentorial primitive neuroectodermal tumor, pituitary tumor, somatostatin secreting tumor, endoderm sinus tumor Carcinoid, central cerebral astrocytoma, glucagonoma, hepatocellular adenoma, insulinoma, medullary epithelioma, plasmacytoma, bipoma and pheochromocytoma. In certain embodiments, the neoplasm is selected from the group consisting of: intraepithelial neoplasia, multiple myeloma / plasma cell neoplasm, plasma cell neoplasm, intraepithelial squamous cell neoplasm Endometrial hyperplasia, localized nodular hyperplasia, hemangioendothelioma, and malignant thymoma.

  In certain other embodiments, the lymphoma is selected from the group consisting of: nervous system lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, non-Hodgkin lymphoma, lymphoma and Waldenstrom's macroglobulinemia. In certain embodiments, the lymphoma is low grade lymphoma. In certain embodiments, the low grade lymphoma is one or more of follicular lymphoma, CLL / SLL, MALT, MZL marginal zone and Waldenstrom's macroglobulinemia. In certain preferred embodiments, the melanoma is selected from the group consisting of: terminal melanoma, superficial enlarged melanoma, uveal melanoma, malignant melanoma-derived melanoma, melanoma, intraocular melanoma, Adenocarcinoma Nodular melanoma and hemangioma. In certain embodiments, the sarcoma is selected from: adenoma, adenosarcoma, chondrosarcoma, endometrial stromal sarcoma, Ewing sarcoma, Kaposi sarcoma, leiomyosarcoma, rhabdomyosarcoma, sarcoma, Uterine sarcoma, osteosarcoma, neurofibrosarcoma, malignant peripheral nerve sheath tumor (MPNST) and pseudosarcoma. In some embodiments, in the method of claim 3, the glioma is selected from the group consisting of: glioma, brain stem glioma, and glioma of the hypothalamus and visual pathway. In some other embodiments, the blastoma is selected from the group consisting of: pulmonary blastoma, pleuropulmonary blastoma, retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, And hemangioblastoma.

  In one embodiment, a method of treating or preventing cancer in a patient comprises administering to the patient a bendamustine and histone deacetylase (HDAC) inhibitor, wherein the cancer is mantle cell lymphoma, diffuse large cell Type B cell lymphoma, low-grade lymphoma, multiple myeloma, or colon cancer.

  In certain embodiments, administration of bendamustine and a histone deacetylase (HDAC) inhibitor is simultaneous. In certain other embodiments, the administration of bendamustine and the histone deacetylase (HDAC) inhibitor is sequential, and bendamustine is administered first. In certain embodiments, the administration of bendamustine and histone deacetylase (HDAC) inhibitor is sequential, with the HDAC inhibitor being administered first. In other embodiments, the administration of bendamustine and the HDAC inhibitor is staggered.

  In certain embodiments, a method of treating or preventing cancer in a patient comprises administering bendamustine and a histone deacetylase (HDAC) inhibitor to the patient, wherein the HDAC inhibitor is: N-hydroxy-4- [2- (4-methoxyquinolin-2-ylcarbonylamino) ethoxy] benzamide, N-hydroxy-4- [2S- (trans-cinnamoylamino) butoxy] benzamide, N- Hydroxy-4- [2R- (trans-cinnamoylamino) butoxy] benzamide, N-hydroxy-4- {2- [4- (2-methoxyethoxy) quinolin-2-ylcarbonylamino] ethoxy} benzamide N-hydroxy-4- [2S- (V Zothiophen-2-ylcarbonylamino) butoxy] -benzamide, N-hydroxy-4- {2S- [benzofuran-2-ylcarbonylamino] butoxy} benzamide, N-hydroxy-4- {2- [3- (methoxymethyl) ) Benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy -4- {2- [3- (i-propoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- {2- [3- (3-hydroxypropoxymethyl) benzofuran-2- Ylcarbonylamino] ethoxy} -benzamide, N-hydride Xyl-4- {2- [3- (2-methoxyethyloxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (pyrrolidin-1-ylmethyl) Benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (piperidin-1-ylmethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4 -{2- [3- (4-Methylpiperazin-1-ylmethyl) benzofuran-2-ylcarbonylamino] -ethoxy} benzamide, N-hydroxy-4- {2- [5- (tetrahydropyran-4-yloxy) Benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy -4- {2- [5- (2-pyrrolidin-1-ylethyloxy) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2S- [5- (2-pyrrolidine- 1-ylethyloxy) benzofuran-2-ylcarbonylamino] butoxy} -benzamide, N-hydroxy-4- {2- [5- (2-pyrrolidin-1-ylethyloxy) benzofuran-2-ylcarbonylamino] -1R-methyl-ethoxy} benzamide, N-hydroxy-4- {2-[(3- (benzofuran-2-yl) -4- (dimethylamino) -but-2-enoyl) amino] -ethoxy } Benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the HDAC inhibitor is the HCl salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide. .

  In certain embodiments, a pharmaceutical composition comprising bendamustine and an HDAC inhibitor is provided, wherein the combination of bendamustine and an HDAC inhibitor is suitable for separate, sequential and / or simultaneous administration. In certain embodiments, the individual is pre-treated with an HDAC inhibitor prior to administration of bendamustine. In some embodiments, an effective amount of the HDAC inhibitor is administered for a period of up to 1 week prior to treatment with bendamustine. In some embodiments, an effective amount of the HDAC inhibitor is administered for a period of up to 5 days prior to administration of an effective amount of bendamustine. In some embodiments, an effective amount of the HDAC inhibitor is administered for a period of 1 to 3 days prior to administration of an effective amount of bendamustine. In some embodiments, the effective amount of the HDAC inhibitor is administered for a period of up to 1-2 weeks prior to administration of an effective amount of bendamustine. In one embodiment, the effective amount of the HDAC inhibitor is administered 24 hours prior to administration of an effective amount of bendamustine.

  In one embodiment, the method of inhibiting tumor growth comprises contacting the tumor with an amount of bendamustine and histone deacetylase (HDAC) inhibitor effective to inhibit tumor growth.

  In another embodiment, the pharmaceutical composition is a solid dosage form suitable for oral administration and the pharmaceutical composition is Compound 1 active ingredient:

Or a pharmaceutically acceptable salt thereof and another active ingredient which is bendamustine or a pharmaceutically acceptable ester, salt or solvate thereof and at least one pharmaceutically acceptable potentiate. Contains form. In certain embodiments, the salt is a tosylate salt. In certain embodiments, the composition is a controlled release oral solid pharmaceutical composition. In certain embodiments of this solid dosage form pharmaceutical composition, one or more active ingredients are present as a salt, wherein the pharmaceutical composition comprises (i) from about 6 hours to about 10 hours after oral administration of said active ingredient to a human. Pulsed at a constant rate over time, (ii) decreasing the rate over about 6 hours to about 10 hours after oral administration to a human, or (iii) about 6 hours to about 10 hours after oral administration to a human And release completely. In certain embodiments, the salt is a tosylate salt. In certain other embodiments, the controlled release oral solid dosage form pharmaceutical composition is one that releases less than about 10% of the active ingredient in the stomach after oral administration to a human.

  In certain embodiments, a controlled release oral solid dosage form pharmaceutical composition comprises an active ingredient in a controlled release matrix. In certain other embodiments, the pharmaceutical composition is in the form of a tablet comprising an enteric coating. In other embodiments, the pharmaceutical composition comprises particles of the active ingredient.

  In other embodiments, the pharmaceutical composition comprises about 10 to about 1000 mg, about 25 to about 600 mg, about 50 to about 200 mg, and about 100 mg of each active ingredient. In a further embodiment, the pharmaceutical composition is suitable for separate, sequential and / or simultaneous administration of bendamustine and an HDAC inhibitor.

  In one aspect, a method of treating human cancer is described, the method comprising daily administration of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor for 5-9 consecutive days, followed by HDAC. Administering a pharmaceutical composition comprising an HDAC inhibitor to a human in a cycle comprising 2 to 7 consecutive drug holidays of the pharmaceutical composition comprising the inhibitor. In some embodiments, a method of treating human cancer comprises the following steps: 5-9 consecutive daily administrations of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor, followed by Administering a pharmaceutical composition comprising an HDAC inhibitor to a human in a cycle comprising 5 to 7 consecutive drug holidays of the pharmaceutical composition comprising the HDAC inhibitor.

  In some embodiments, daily administration of 5-9 consecutive days of a pharmaceutical composition comprising an HDAC inhibitor comprises: administration of two immediate release pharmaceutical compositions comprising an HDAC inhibitor daily Two immediate release pharmaceutical compositions are administered sequentially, and the second immediate release pharmaceutical composition is administered about 4-6 hours after administration of the first immediate release pharmaceutical composition, daily Administration or daily administration of a pharmaceutical composition in a single controlled release oral solid dosage form containing an HDAC inhibitor.

  In some embodiments, 5-9 consecutive consecutive administrations of a pharmaceutical composition comprising an HDAC inhibitor is effective plasma concentration of the HDAC inhibitor in a human for at least about 6 hours on the day of dosing. Daily administration of a sufficient amount of an HDAC inhibitor to maintain In some embodiments, administration of 5-9 consecutive consecutive days of a pharmaceutical composition comprising an HDAC inhibitor is at least about 6 hours (but not more than 14 consecutive hours) on the day of dosing. ), Including daily administration of an amount of the HDAC inhibitor sufficient to maintain an effective plasma concentration of the HDAC inhibitor in humans.

  In some embodiments, 5-9 consecutive consecutive administrations of a pharmaceutical composition comprising an HDAC inhibitor is effective for the HDAC inhibitor in humans for at least about 6-8 hours on the day of dosing. Includes daily administration of an amount of an HDAC inhibitor sufficient to maintain plasma concentrations.

  In some embodiments, 5-9 consecutive consecutive administrations of a pharmaceutical composition comprising an HDAC inhibitor comprises: two immediate release pharmaceutical compositions comprising an HDAC inhibitor are 4-6 hours Daily administration of two immediate release pharmaceutical compositions administered sequentially, or daily administration of a single controlled release oral solid dosage form pharmaceutical composition comprising an HDAC inhibitor.

  In some embodiments, a single controlled release oral solid dosage form pharmaceutical composition comprising an HDAC inhibitor comprises two immediate doses comprising an HDAC inhibitor administered sequentially in 4-6 hours. Providing in vivo release in humans substantially the same as a releasable pharmaceutical composition.

  In some embodiments, the HDAC inhibitor is: N-hydroxy-4- [2- (4-methoxyquinolin-2-ylcarbonylamino) ethoxy] benzamide, N-hydroxy-4- [2S -(Trans-cinnamoylamino-butoxy) benzamide, N-hydroxy-4- [2R- (trans-cinnamoylamino-butoxy] benzamide, N-hydroxy-4- {2- [4- (2-methoxyethoxy) quinolin-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- [2S- (benzothiophen-2-ylcarbonylamino) butoxy] benzamide, N-hydroxy-4- {2S- [Benzofuran-2-ylcarboni Amino] butoxy} benzamide, N-hydroxy-4- {2- [3- (methoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- {2- [3- (N, N -Dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (i-propoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N- Hydroxy-4- {2- [3- (3-hydroxypropoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (2-methoxyethyloxymethyl) Benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N- Droxy-4- {2- [3- (pyrrolidin-1-ylmethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (piperidin-1-ylmethyl) benzofuran 2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (4-methylpiperazin-1-ylmethyl) benzofuran-2-ylcarbonylamino] -ethoxy} benzamide, N-hydroxy -4- {2- [5- (tetrahydropyran-4-yloxy) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [5- (2-pyrrolidin-1-yl) Ethyloxy) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N- Hydroxy-4- {2S- [5- (2-pyrrolidin-1-ylethyloxy) benzofuran-2-ylcarbonylamino] butoxy} -benzamide, N-hydroxy-4- {2- [5- (2-pyrrolidine -1-ylethyloxy) benzofuran-2-ylcarbonylamino] -1R-methyl-ethoxy} benzamide, N-hydroxy-4- {2-[(3- (benzofuran-2-yl) -4- (dimethylamino) ) -But-2-enoyl) amino] -ethoxy} benzamide, or a pharmaceutically acceptable salt thereof.

  In some embodiments, the HDAC inhibitor is the HCl salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide. .

  In some embodiments, the HDAC inhibitor is a tosylate salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide. .

  In some embodiments, 5 of the pharmaceutical composition comprising an HCl salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide Daily administration for -9 consecutive days includes: Two immediate release pharmaceutical compositions containing the HCl salt of Compound 1 are administered 4-6 hours apart, each day of two immediate release pharmaceutical compositions Or daily administration of a single controlled release oral solid dosage form pharmaceutical composition.

  In some embodiments, 5 of the pharmaceutical composition comprising an HCl salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide Daily administration for ˜9 consecutive days is from about 10 mg of HCl salt of N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide. Includes daily administration of about 300 mg.

  In some embodiments, the cancer is a hematological cancer, a solid tumor, or a sarcoma. In some embodiments, the cancer is breast cancer, colon cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, bladder cancer, gastric cancer, gastrointestinal stromal Tumor, pancreatic cancer, germ cell tumor, mastocytoma, neuroblastoma, mastocytosis, testicular cancer, glioblastoma, astrocytoma, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non Hodgkin lymphoma, low grade lymphoma, melanoma, myeloma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, and chronic myelogenous leukemia.

  In some embodiments, the method comprises a DNA damaging agent, a topoisomerase I or II inhibitor, an alkylating agent, a PARP inhibitor, a proteasome inhibitor, an RNA / DNA antimetabolite, a mitotic inhibitor, an immunomodulator, Angiogenesis inhibitor, aromatase inhibitor, hormone regulator, apoptosis inducer, kinase inhibitor, monoclonal antibody, abarelix, ABT-888, aldesleukin, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine ana Arfostine anastrozole, arsenic trioxide, asparaginase, azacitidine, AZD-2281, bendamustine, perifosine, lenalidomide, chloroquine, bevacizumab Bexarotene, bleomycin, bortezomib, BSI-201, busulfan, busulfan, carsterone, capecitabine, carboplatin, carfilozib, carmastine, carmastine, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphabin Cytarabine liposome, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin liposome, daunorubicin, decitabine, denileukine, dexrazoxane, docetaxel, doxorubicin, doxorubiporin doporbine doporbine doporbine doporbine Rulotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, hydroxyurea , Ibritumomab tiuxetane, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, interferon alfa 2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlormetamine, megestrolcaptomelfuran Purine, methotrexate, methoxalene, mitomycin C, mitomycin C, mitotane, mitoxan Ron, nandrolone fenpropionate, nelarabine, NPI-0052, nofetumomab (nofetumomab), oprelplatin, oxaliplatin, paclitaxel, paclitaxel protein-binding particles, paliferin, pamidronate, panitumumab, pegademase, pegaspalgase, pegfilgrastim Sodium, pentostatin, pipobrommann, pricamycin, mitramycin, porfimer sodium, procarbazine, quinacrine, RAD001, rasburicase, rituximab, sargramostim, sargramostim, sorafenib, streptozocin, sunitinib malate, tamoxifen, temolidomide test , Thioguanine, thiotepa At least one additional treatment selected from topotecan, toremifene, tositumomab, tositumomab / I-131 tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zoledronate, and zoledronic acid Further comprising the step of administering. In certain embodiments, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with bendamustine and rituximab.

  In some embodiments, the method further comprises radiation therapy.

  In one embodiment, the method includes administering an alkylating agent to the human in combination with the HDAC inhibitors disclosed herein. In one embodiment, the alkylating agent is bendamustine. In another embodiment, the method comprises administering to a human bendamustine, also known as ribomustin or treanda, in combination with an HDAC inhibitor.

  In one embodiment, the HCl salt of N-hydroxy-4- {2- [3- [N (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide (Compound 1) and at least one pharmaceutical agent Of a pharmaceutical composition comprising an HCl salt of Compound 1 followed by daily administration of the pharmaceutical composition comprising the HCl salt of Compound 1 for 5-9 consecutive days, followed by Described herein is a method for treating cancer comprising administering to a human in a cycle consisting of 5-7 consecutive drug holidays. In some embodiments, 5-9 consecutive days of administration of a pharmaceutical composition comprising the HCl salt of Compound 1 is the administration of two immediate release doses of the pharmaceutical composition comprising the HCl salt of Compound 1 daily. Where the two immediate release doses are administered 4-6 hours apart.

  In some embodiments, daily administration of a pharmaceutical composition comprising the HCl salt of Compound 1 for 5-9 consecutive days is a single controlled release oral solid formulation, as described herein. Administering a pharmaceutical composition in the form.

  In some embodiments, daily administration of a pharmaceutical composition comprising the HCl salt of Compound 1 for 5-9 consecutive days comprises about 10 mg to about 300 mg of the HCl salt of Compound 1.

  In one aspect, a method of treating cancer using an HDAC inhibitor as described herein reduces the incidence of human grade 4 thrombocytopenia in cancer.

  In one aspect, the use of the HCl salt of Compound 1 is in the manufacture of a controlled release pharmaceutical composition that is administered orally to a human with cancer.

  In one aspect, the use of a controlled release pharmaceutical composition of the HCl salt of Compound 1 is for treating human cancer.

  In one aspect, a dosing regimen of the pharmaceutical composition is used in the treatment of human cancer, wherein the pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, and the dosing regimen comprises cancer. Reduce the incidence of human grade 4 thrombocytopenia.

  In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof,

And a controlled release oral solid dosage form pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is about 6 after oral administration to humans. Compound 1 or a pharmaceutically acceptable salt thereof is completely released over a period of about 10 hours.

  In one aspect, Compound 1 is in the pharmaceutical composition as the HCl salt (Compound 1 (HCl)). In some embodiments, Compound 1 is in the pharmaceutical composition as a tosylate salt.

  In some embodiments, the pharmaceutical composition is (i) at a constant rate from about 6 hours to about 10 hours after oral administration to a human, and (ii) from about 6 hours to about 10 hours after oral administration to a human. Compound 1 (HCl) is completely released in pulses over 10 hours with decreasing rates or (iii) from about 6 hours to about 10 hours after oral administration to humans.

  In some embodiments, the pharmaceutical composition completely releases Compound 1 (HCl) within 10 hours after oral administration to a human.

  In some embodiments, the pharmaceutical composition releases less than about 10% of Compound 1 (HCl) in the stomach after oral administration to a human.

  In some embodiments, the pharmaceutical composition does not release Compound 1 (HCl) in the stomach after oral administration to a human.

  In some embodiments, the pharmaceutical composition comprises Compound 1 (HCl) in a controlled release matrix.

  In some embodiments, the pharmaceutical composition is in the form of a tablet comprising an enteric coating.

  In some embodiments, the enteric coating comprises: hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose Ester ether phthalate, hydroxypropyl cellulose phthalate, alkali salt of cellulose acetate phthalate, alkaline earth salt of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, sodium carboxymethylcellulose, acrylic acid polymers and copolymers, ethyl acrylate / Methyl methacrylate / ethyltrimethylan Nium chloride methacrylate terpolymer, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer; shellac, Shellac, shellac acetyl alcohol or shellac n-butyl stearate treated with ammonia.

  In some embodiments, the pharmaceutical composition comprises particles of Compound 1 (HCl).

  In some embodiments, the pharmaceutical composition fully releases Compound 1 (HCl) in pulses over about 6 hours to about 10 hours.

  In some embodiments, the pharmaceutical composition comprises at least two different groups of particles of Compound 1 (HCl).

  In some embodiments, the pharmaceutical composition comprises a first group of delayed release particles of Compound 1 (HCl) and a second group of delayed release particles of Compound 1 (HCl).

  In some embodiments, the delayed release particles of Compound 1 (HCl) are in the form of beads, pellets, granules, or minitablets.

  In some embodiments, the first group of Compound 1 (HCl) delayed release particles delays the release of Compound 1 (HCl) for at least 1-2 hours after oral administration to a human.

  In some embodiments, a second group of Compound 1 (HCl) delayed release particles delays the release of Compound 1 (HCl) for at least 3-6 hours after oral administration to a human.

  In some embodiments, the release of Compound 1 (HCl) from the second group of delayed release particles is the amount of Compound 1 (HCl) from the first group of delayed release particles after administration to a human. At least half is released and occurs 2-6 hours later.

  In some embodiments, the pharmaceutical composition releases Compound 1 (HCl) in two pulses, wherein a second pulse of Compound 1 (HCl) is administered after Compound 1 (HCl) after oral administration to a human. ) Occurs 2 to 6 hours after the first pulse.

  In some embodiments, the amount of Compound 1 (HCl) is the same for the two groups of particles.

  In some embodiments, the delayed release coating in the first group of delayed release particles is different from the delayed release coating of the second group of delayed release particles.

  In some embodiments, the delayed release coating comprises a pH sensitive coating or a pH insensitive coating.

  In some embodiments, the pharmaceutical composition is in the form of pellets, beads, granules, or minitablets in a capsule.

  In some embodiments, the pharmaceutical composition is in the form of pellets, beads, or granules that are compressed into a single tablet.

  In some embodiments, the pharmaceutical composition comprises from about 10 mg to about 300 mg of Compound 1 (HCl).

In some embodiments, the pharmaceutical composition is about 0.0035 to 0.0124 (μM · h) / (mg / m ² ) dose normalized mean AUC _0-8h when administered orally to a human. I will provide a.

  In one aspect, the pharmaceutical composition is used in the treatment of human cancer. In some embodiments, the cancer is a hematological cancer, a solid tumor, or a sarcoma. In some embodiments, the cancer is breast cancer, colon cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, bladder cancer, gastric cancer, gastrointestinal stromal Tumor, pancreatic cancer, germ cell tumor, mastocytoma, neuroblastoma, mastocytosis, testicular cancer, glioblastoma, astrocytoma, lymphoma, melanoma, myeloma, acute myeloid leukemia ( AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, and chronic myelogenous leukemia. In one aspect, the cancer is lymphoma or leukemia. In one aspect, the cancer is B cell lymphoma, T cell lymphoma, low grade lymphoma, Hodgkin lymphoma or non-Hodgkin lymphoma. In one aspect, the cancer is non-Hodgkin lymphoma.

  In some embodiments, the pharmaceutical composition is used in combination with radiation therapy.

  In some embodiments, the pharmaceutical composition comprises a DNA damaging agent, topoisomerase I or II inhibitor, alkylating agent, PARP inhibitor, proteasome inhibitor, RNA / DNA antimetabolite, mitotic inhibitor, immunomodulator Agent, angiogenesis inhibitor, aromatase inhibitor, hormone regulator, apoptosis inducer, kinase inhibitor, monoclonal antibody, abarelix, ABT-888, aldesleukin, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifos Chin anastrozole arsenic trioxide, asparaginase, azacitidine, AZD-2281, bendamustine, perifosine, lenalidomide, chloroquine, bevaci Zumab, Bexarotene, Bleomycin, Bortezomib, BSI-201, Busulfan, Busulfan, Carsterone, Capecitabine, Carboplatin, Carfilzomib (carfilozib), Carmastine, Carmastine, Celecoxib, Cetuximab, Chlorambutyl, Cisplatin, Cladifine, Cladobin Cytarabine, cytarabine liposome, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin liposome, daunorubicin, decitabine, denileukine, dexrazoxane, docetaxel, doxorubiporin doxorubicin doxorubicin Rufa, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, Hydroxyurea, ibritumomab tiuxetane, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechloretamine acetate, megestrol acetate Faran, mercaptopurine, methotrexate, methoxalene, mitomycin C, mitomycin C, mitotane Mitoxantrone, nandrolone fenpropionate, nelarabine, NPI-0052, nofetumomab (nofetumomab), oprelbequin, oxaliplatin, paclitaxel, paclitaxel protein-binding particles, palifermin, pamidronate, panitumumab, pegadempalzem, pegaspirgrazem Pemetrexed disodium, pentostatin, pipobroman, pricamycin, mitramycin, porfimer sodium, procarbazine, quinacrine, RAD001, rasburicase, rituximab, sargramostim, sargramostim, sorafenib, streptozocin, sunitinib malate, tamoxifen, temomid , Thalidomide, thiogue Nin, thiotepa, topotecan, toremifene, tositumomab, tositumomab / I-131 tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zoledronate, and at least one additional treatment Used in combination with drugs.

  A HDAC inhibitor compound described herein within a packaging material and a compound or composition, or a pharmaceutically acceptable thereof, effective to selectively inhibit histone deacetylase activity Acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates may provide histone deacetylase activity. A label indicating that it is used to inhibit, or to treat, prevent, or alleviate one or more symptoms of a disease or disorder that would benefit from inhibition of histone deacetylase activity Including products are provided.

  In some embodiments, a pharmaceutical composition described herein comprising an HDAC inhibitor is formulated in a manner suitable for oral administration to humans.

  In some embodiments, a pharmaceutical composition described herein comprising an HDAC inhibitor is formulated in a manner suitable for intravenous administration to a human.

  Other objects, features, and advantages of the methods, compounds, and compositions described herein will become apparent from the following detailed description. However, while the detailed description and specific examples illustrate specific embodiments, various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. It will be understood that these are given for illustrative purposes only.

Results of in vitro dosing schedule studies are shown. The effect of the HDAC inhibitor (ie, Compound 1) dosing schedule on tumor cell death has been shown. The results of modeling the administration schedule of Compound 1 and the effects on the Jurkat cell line and the HCT116 cell line are shown. 3 shows the results from treatment of solid tumors, particularly hCT-116 colon cancer tumors, with bendamustine and an HDAC inhibitor (ie Compound 1). The effect of the combination of each active agent at different dosage levels with bendamustine and an HDAC inhibitor (ie Compound 1) is shown. FIG. 5 shows the results of treatment of U266 multiple myeloma cells with bendamustine and an HDAC inhibitor (ie, Compound 1) as studied by monitoring apoptosis using flow cytometry. The effect of the combination of each active agent at different dosage levels with bendamustine and an HDAC inhibitor (ie Compound 1) is shown. FIG. 5 shows the results of treatment of DLCL2 lymphoma cells with bendamustine and an HDAC inhibitor (ie, Compound 1) as studied by monitoring apoptosis using flow cytometry. 5A depicts the effect of the combination of each active agent at different dose levels with bendamustine and an HDAC inhibitor (ie, Compound 1). 5B shows the effect of a combination of bendamustine and an HDAC inhibitor (ie, Compound 1) with each active agent at different dosage levels, and treatment of the combination with bendamustine and an HDAC inhibitor (ie, Compound 1). One day ago, lymphoma cells are pretreated with an HDAC inhibitor (ie, Compound 1) one day. FIG. 5 shows the role of RAD51 in the synergistic anticancer activity of bendamustine and HDAC inhibitor (ie, Compound 1). 6A reveals suppression of RAD51 expression in two multiple myeloma cell lines treated with an HDAC inhibitor (ie Compound 1) and a combination of an HDAC inhibitor (ie Compound 1) and bendamustine Western blot is shown. 6B-6C shows the effect of a combination of bendamustine and an HDAC inhibitor (ie Compound 1) in two multiple myeloma cell lines as studied by monitoring flow cytometry of apoptosis. FIG. 6 shows changes in tumor volume in female SCID mice after individual treatment with HDAC inhibitors (ie, Compound 1), bendamustine, and a combination of bendamustine and HDAC inhibitors (ie, Compound 1). FIG. 6 shows H929 multiple myeloma cells treated with HDAC inhibitors described herein (ie, Compound 1) (200 nM) and / or bendamustine (50 uM) for 1-3 days. Additional sequences were tested by first adding bendamustine or an HDAC inhibitor (ie, Compound 1) and adding the other 24 hours later. The HDAC inhibitor (ie Compound 1) and bendamustine 24 hours later caused the most cell death in this series. Pretreatment with the HDAC inhibitors described herein (ie, Compound 1) suppressed up-regulation of RAD51 caused by bendamustine, thereby inhibiting DNA damage repair and enhancing the effects of bendamustine It is shown that. FIG. 9 shows the effective synergy of the HDAC inhibitor described herein (ie, Compound 1) with bortezomib in neuroblastoma. FIG. 4 shows the synergistic action of the HDAC inhibitor described herein (ie, Compound 1) with chloroquine, an autophagy inhibitor. Perifosine has been shown to be synergistic with HDAC inhibitors (ie Compound 1) in colon tumor cells. The HDAC inhibitors described herein (ie, Compound 1) have been shown to be synergistic with all concentrations of cisplatin in platinum-resistant ovarian tumor cell lines.

  Cancer is considered a gene-deficient disease, such as gene mutations and deletions, as well as chromosomal abnormalities that result in loss of function of tumor suppressor genes and / or gain or overactivation of oncogene function. It has been.

  Cancer is characterized by genome-wide changes in gene expression within the tumor. These changes promote the ability of tumors to evolve through the cell cycle, avoid apoptosis, or become resistant to chemotherapy. HDAC inhibitors can reverse some of these changes and restore a pattern such as that of normal cells.

  The human genome consists of a complex network of genes that switch genes on and off depending on the needs of the cell. One way to switch genes on or off uses chemical modification of histone proteins. Histone proteins are structural components of chromosomes and form scaffolds on which DNA, which is genetic material, is placed. Well-studied histone modifications are modifications that are catalyzed by acetylation and deacetylation, a family of enzymes also known as histone acetyltransferases and histone deacetylases.

  Inhibition of the HDAC enzyme by Compound 1 unbalances in favor of an acetylated state, ie, a state that allows transcription to occur (which can be considered as “switching on” the gene). When cells are treated with Compound 1, the first wave of genes that have calmed down is switched on first. Some of these genes are themselves regulators and activate or suppress the expression of additional genes. The result is an orchestra of changes in gene expression: some genes are switched on and others remain switched off.

  After chemotherapy and / or radiation therapy, some of the patient's tumors switch on certain genes as a strategy by the tumor to become compatible with treatment and become resistant to cell death. One example of a genetic change that occurs in many cancers is the activation of the DNA repair gene RAD51. In response to chemotherapy or radiation treatment that damages DNA, tumors switch DNA repair genes (including RAD51) as an adaptive strategy to help repair DNA damage given by these agents. Is often included. In preclinical models, Compound 1 switches off RAD51 (and other DNA repair genes), effectively inhibiting the tumor's ability to repair damaged DNA, and against chemotherapy and radiation. Sensitize the tumor.

(Preclinical activity of HDAC inhibitors)
Preclinical studies have shown that HDAC inhibitors such as Compound 1 have anticancer activity with tumor specificity. These studies provided important information regarding the in vitro and in vivo activities of HDAC inhibitors such as Compound 1 and determined the molecular mechanisms underlying the anticancer effects.

  In vitro: Compound 1 is active against many tumor cell lines and is effective in mouse models of lung, colon, prostate, pancreas and brain tumors.

  Ex vivo: Compound 1 is active in the major human tumors from patients with colon, ovary, lung, and many blood cancers.

  Extensive safety and toxicology studies have been conducted in many animal species. The mechanism of action of Compound 1 has been studied and multifaceted attacks on tumor cells: up-regulation of p21 and other tumor suppressors and cell cycle genes, induction of reactive oxygen species and attenuation of antioxidant pathway, calcium homeostasis Changes in RNA and increased ER stress, down-regulation of DNA repair pathways and increased DNA damage, direct induction of apoptosis by cell death receptors and caspase activation.

  Compound 1 is a hydroxamate-based HDAC inhibitor. Described herein are pharmaceutical compositions comprising Compound 1, as well as methods, pharmacokinetic and pharmacodynamic strategies, dosing regimens for treating human cancer as either monotherapy or combination therapy.

(Therapeutic and pharmacodynamic effects of Compound 1)
In trials involving humans with cancer, Compound 1 in solution form was administered at 2 mg / kg as a single oral dose and as multiple 2-hour IV infusion doses. The systemic exposure measured as AUC _0-∞ for IV and oral administration was 5.9 μM * hr and 1.45 μM * hr, respectively, indicating about 27% oral bioavailability in humans.

  The therapeutic effect of an HDAC inhibitor (eg, Compound 1) is as follows: HDAC inhibitor is orally administered twice a day (two doses are administered sequentially at about 4 to about 6 hours). It is achieved in cancerous humans by administering three times a day (three doses are administered continuously at about 4 to about 6 hours), intravenously or continuously. The aforementioned dosing regimen promotes the ability to maintain effective plasma concentrations of HDAC inhibitors in humans for at least 6 consecutive hours.

  The therapeutic effect of Compound 1 is that by administering Compound 1 (immediate release oral capsule) twice a day (two doses are given continuously in about 4 to about 6 hours), Achieved in humans. In some embodiments, dosing twice a day reduces the incidence of thrombocytopenia compared to dosing three times a day.

  For therapeutic effects, an effective plasma concentration of Compound 1 in humans must be maintained on the day of dosing for at least 6 consecutive hours, at least 7 consecutive hours, or at least 8 consecutive hours on each day. For therapeutic effects, the effective plasma concentration of Compound 1 in humans must be maintained for at least 6 consecutive days on each day of dosing. For therapeutic effects, the effective plasma concentration of Compound 1 in humans must be maintained for at least 7 consecutive days on each day of dosing. In some embodiments, for therapeutic effects, an effective plasma concentration of Compound 1 in humans must be maintained from about 6 hours to about 8 hours consecutively each day on the day of dosing. In some embodiments, the effective plasma concentration of Compound 1 in humans must be maintained on the day of dosing for at least 6 hours (but no more than 12, 13 or 14 hours continuously). In some embodiments, maintaining an effective plasma concentration of Compound 1 for at least 6 consecutive hours (but not more than 14 consecutive hours) on the day of dosing is an effect of inhibiting tumor cell growth. To minimize the incidence of thrombocytopenia. In some embodiments, maintaining an effective plasma concentration of Compound 1 for a period of about 6 to about 8 hours on the day of dosing enhances the effect of inhibiting tumor cell growth and reduces thrombocytopenia. Minimize the incidence of symptoms.

  The oral bioavailability of Compound 1 in humans, administered as an immediate release capsule or oral solution, was found to be about 27%. Differences in pharmacokinetics were observed in fasted and fed experimental animals. Compound 1 appears to be preferentially absorbed in the intestine.

  In one embodiment, provided herein is a method of providing a reliable therapeutic and pharmacodynamic effect to an HDAC inhibitor such as Compound 1 or a pharmaceutically acceptable salt thereof, the method comprising: Administering a HDAC inhibitor or a pharmaceutically acceptable salt in the form of a controlled release formulation. Controlled release formulations are possible once on the day of dosing. Controlled release formulations also allow for the release of agents that are active in the gut rather than the stomach (ie, HDAC inhibitors such as Compound 1 or pharmaceutically acceptable salts thereof).

  In one aspect, the controlled release formulation is a multiparticulate drug delivery system. Multiparticulate drug delivery systems are oral dosage forms consisting of a large number of discrete small units, each exhibiting desirable characteristics. In these systems, the amount of drug substance is generally divided into a plurality of small units consisting of thousands of spherical particles with a diameter of 0.05-2.00 mm. Multiparticulate dosage forms are pharmaceutical formulations in which the active substance is present as many small, independent units. These small units can be encapsulated or compressed into tablets to deliver the recommended total dose. Multiparticulates are not very dependent on gastric emptying and therefore there is less variation between and within the subject in gastrointestinal transit time. In addition, multiparticulates are better distributed and less prone to causing local irritation or affected by the presence of food.

  Multiparticulate dosage forms offer benefits such as increased bioavailability, reduced risk of local irritation, and predictable gastric emptying. In some embodiments, the multiparticulate system exhibits replicable pharmacokinetic behavior that is superior to conventional formulations.

  Following the disintegration of a controlled release formulation (eg, a tablet or capsule) that occurs within a few minutes, individual units pass rapidly through the gastrointestinal tract. If these small units have a diameter of less than 2 mm, they can constantly exit the stomach even when the pylorus is closed. These reduce the variation between and within individuals in plasma levels and bioavailability.

  Other controlled release oral pharmaceutical dosage forms can provide the same benefits observed with multiparticulate drug delivery systems.

(Drug holiday)
Thrombocytopenia is a side effect observed in humans who are treated with HDAC inhibitor compounds. Thrombocytopenia is a condition in which there are fewer platelets in the blood than normal. This can make it easier to bruise, cause large amounts of bleeding from wounds, and bleeding from mucous membranes and other tissues. Thrombocytopenia is typically alleviated by reducing the daily dose of HDAC inhibitor compound administered to humans. However, reducing the daily dose of the HDAC inhibitor compound may not achieve therapeutic and pharmacodynamic effects on the HDAC inhibitor compound.

  A dosing regimen for achieving therapeutic and pharmacodynamic effects on HDAC inhibitors while limiting the incidence of grade 4 thrombocytopenia is presented herein, which is provided on each day of dosing. A sufficient amount of HDAC inhibitor administered daily for 5-9 days to maintain an effective plasma concentration of the HDAC inhibitor for at least 6 consecutive hours, followed by continuous administration of the HDAC inhibitor For 5-9 days. In some embodiments, on the day of dosing, an effective plasma concentration of the HDAC inhibitor is at least 6 hours, at least 7 hours, or at least 8 hours, but continuously 12, 13 or 14 hours. Maintained without exceeding. In some embodiments, on the day of dosing, the HDAC inhibitor is administered in an amount sufficient to maintain an effective plasma concentration of the HDAC inhibitor for a continuous period of about 6 hours to about 8 hours. In some embodiments, the HDAC inhibitor is administered orally. In some embodiments, the effective plasma concentration of the HDAC inhibitor is maintained for at least 12, 13, or 14 hours continuously on the day of dosing. In other embodiments, the HDAC inhibitor is administered parenterally.

  Presented herein are dosing regimens for achieving therapeutic and pharmacodynamic effects on HDAC inhibitors while limiting the incidence of Grade 4 thrombocytopenia, which is (a) continuous. 7 days, oral administration of HDAC inhibitor (immediate release oral pharmaceutical composition) twice a day followed by 7 days of drug holiday without administration of HDAC inhibitor, or (b) continuous Thus, for 7 days, an oral administration of an HDAC inhibitor (immediate release oral pharmaceutical composition) once a day followed by 7 consecutive drug holiday days without administration of an HDAC inhibitor. The above dosing regimen further includes 5-9 consecutive days of administration of the HDAC inhibitor followed by 2-9 consecutive days of drug holiday without administration of the HDAC inhibitor.

  Presented herein is a dosing regimen for achieving therapeutic and pharmacodynamic effects on Compound 1 while limiting the incidence of Grade 4 thrombocytopenia, which is (a) continuously 7 days, oral administration of Compound 1 (immediate release oral pharmaceutical composition) twice a day, followed by 7 consecutive drug holidays without administration of Compound 1, (b) 7 consecutive days, It includes once daily administration of Compound 1 (immediate release oral pharmaceutical composition) followed by 7 consecutive drug holiday days without Compound 1 administration. The dosing regimen further includes 5-9 consecutive days of administration of Compound 1 followed by 2-9 consecutive days of drug holiday without administration of Compound 1.

  The dosing regimen further includes 5-9 consecutive days of administration of Compound 1 followed by 2-9 consecutive days of drug holiday without administration of Compound 1.

(HDAC inhibitor compound)
N-hydroxy-4- {2- [3- (N, N-dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide (Compound 1) has the following structure:

  In one aspect, Compound 1 is used in the pharmaceutical compositions and methods described herein as a pharmaceutically acceptable salt. In one embodiment, compound 1 is used as the hydrochloride salt. In one embodiment, compound 1 is used as a tosylate salt.

Further pharmaceutically acceptable salts of Compound 1 include: (a) the acidic proton of Compound 1 is a metal ion, such as an alkali metal ion (eg, lithium, sodium, potassium), alkaline earth Salts formed when replaced by ions (eg, magnesium or calcium) or aluminum ions or when replaced by ammonium cations (NH 4 ⁺ ), (b) ethanolamine, diethanolamine, triethanolamine, tromethamine A salt formed by reacting compound 1 with a pharmaceutically acceptable organic base containing an alkylamine such as N-methylglucamine, dicyclohexylamine, tris (hydroxymethyl) methylamine, and arginine; Like lysine Salts containing an amino acid, (c) providing acid addition salts, salts formed by reacting compound 1 into a pharmaceutically acceptable acid. Pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc., or, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid , Pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, Methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] octa 2-ene-1-carboxylic acid, glucoheptonic acid tonic acid), 4,4′-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, glucone It contains organic acids such as acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

  Additional pharmaceutically acceptable salts can be found in Berge et al. , J. et al. Pharm. Sci. 1977, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stah and Wermuth, Ed. Wiley-VCH and VHCA, Zurich, 2002. It is described in.

  In some embodiments, sites on the aromatic ring portion of the compounds described herein that are susceptible to various metabolic reactions are modified so that various metabolic reactions are reduced and minimized, Or it is removed. Such modifications include, by way of example, incorporation of appropriate substituents on aromatic ring structures such as halogen, deuterium and the like. In one aspect, the HDAC inhibitor compounds described herein are deuterated at sites that are susceptible to metabolic reactions.

The compounds described herein include compounds labeled with the same isotopes as listed in the various formulas and structures presented herein, but one or more atoms are naturally and commonly found. It is replaced with one atom having an atomic mass or mass number different from the atomic mass or mass number to be produced. Examples of isotopes that can be incorporated into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively. ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl. Compounds labeled with the specific isotopes described herein, eg, those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful for analysis of drug and / or substrate tissue distribution. In addition, substitution with isotopes such as deuterium (ie ² H) may result in certain therapeutic benefits due to superior metabolic stability, for example, increased in vivo half-life or reduced dosage requirements Can do.

  Other HDAC inhibitor compounds used in the pharmaceutical compositions, pharmacokinetic strategies, dosing regimens, methods of treatment, and combination therapies described herein include compounds comprising a structure of formula (I): Or a pharmaceutically acceptable salt thereof,

here,
X is —O—, —NR ² —, or S (O) _n , n is 0, 1, or 2, R ² is hydrogen, —CH ₃ , —CH ₂ CH ₃ ;
Y represents ethylene, propylene, 1-methylpropylene, 2-methylpropylene, —CH (C ₂ H ₅ ) CH ₂ —, —CH (CH (CH ₃ ) ₂ ) CH ₂ —, and —CH (CH ₃ ). CH ₂ - and is,
R ³ is hydrogen, —CH ₃ , or —CH ₂ CH ₃ ;
Ar is phenyl, naphthyl, quinolinyl, benzofuranyl, benzothienyl, transphenyl CH═CH—, or trans (benzofuran-2-yl) CH═CH—, where Ar is chloro, fluoro , Trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, -OH, 1-cyclopropylpiperidin-4-yloxy, 1- (2,2,2-trifluoroethyl) piperidin-4-yloxy, N , N-dimethylaminomethyl, N, N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, 2-methoxyethoxy, 2-morpholin-4-ylethoxy, pyridin-3-ylmethoxy, 2-hydroxyethoxy, 2-N, N-di Methylaminoethoxy, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl, 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyl Oxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluorophenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxy Methyl, 4- [1.2.4-triazin-1-yl-phenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-trifluoromethylpiperidin-1-ylmethyl, 4- Methylpiperazine-1-ylmethy 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridin-3-ylmethyloxymethyl, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethyloxy, 2-pyrrolidin-1-ylethyloxy, piperidin-4-yloxy, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl-methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2- (4-trifluoromethylphenyl) ethyl , 2- (3-Triflu B methoxyphenyl) ethyl, N- hydroxyamino carbonyl - methylaminomethyl, or 3- (2-carboxyethyl amino - optionally substituted with one or two substituents independently selected from methyl).

  In some embodiments, Ar is benzofuran-2-yl and N, N-dimethylaminomethyl, N, N-diethylaminomethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy- Methyl, hydroxyl-4-yloxymethyl, 2,4,6-trifluorophenoxy-methyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxy-methyl, 4-imidazol-1-yl Phenoxy-methyl, 4- [1.2.4-triazin-1-yl-phenoxymethyl, 2-phenylethyl, 3-hydroxypropyloxymethyl, 2-methoxyethyloxymethyl, pyrrolidin-1-ylmethyl, piperidine-1 -Ilmethyl, 4-trifluoromethylpiperidin-1-ylmethyl 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, 2- (3-trifluoro Methoxyphenylethyl), N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropyl-thiomethyl, 3-hydroxypropylsulfinyl-methyl, 3-hydroxypropylsulfonylmethyl, Benzofura containing N-methyl-N-2-indol-3-ylethylaminomethyl, 2- (4-trifluoromethylphenyl) ethyl, N-hydroxyaminocarbonyl-methylaminomethyl, or 2-carboxyethylaminomethyl It is mono-substituted with 3-position of the 2-yl ring.

  In some embodiments, Ar is benzofuran-2-yl and N, N-dimethylaminomethyl, N, N-diethylaminomethyl, 2-methoxyethoxymethyl, methoxymethyl, 3-i-propoxymethyl, morpholine- Mono-substituted at the 3-position of the benzofuran-2-yl ring, including 4-ylmethyl, 3-hydroxypropyloxymethyl, 3-methoxypropyloxymethyl, pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl.

  In some embodiments, Ar is benzofuran-2-yl, 1-cyclopropylpiperidin-4-yloxy, piperidin-4-yloxy, tetrahydropyran-4-yloxy, 2,2,2-trifluoroethoxy, Substituted at the 5-position of the benzofuran-2-yl ring including 2-pyrrolidin-1-ylethyloxy or 1- (2,2,2-trifluoroethyl) piperidin-4-yloxy.

  In some embodiments, Ar is transphenyl CH═CH—, wherein phenyl is one selected independently from methyl, ethyl, methoxy, ethoxy, methylenedioxy, or —OH, or Optionally substituted with two substituents. In some embodiments, Ar is transphenyl CH═CH—.

  In some embodiments, Ar is naphthyl, which is optionally substituted with one or two substituents.

  In some embodiments, Ar is quinolinyl and quinolinyl is optionally substituted with one or two substituents.

  In some embodiments, Ar is quinolinyl, which is chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, —OH, 2-methoxyethoxy, 2-hydroxyethoxy, methoxy 1 or 2 substituents independently selected from methyl, 3-i-propoxymethyl, 3-hydroxypropyloxymethyl, 3-methoxypropyloxymethyl, or 3,3,3-trifluoropropyloxymethyl Optionally substituted.

In some embodiments, X is —O— and R ³ is hydrogen.

In some embodiments, X is —S (O) _n and R ³ is hydrogen.

In some embodiments, Y is ethylene. In some embodiments, Y is ethylene or —CH (C ₂ H ₅ ) CH ₂ —. In some embodiments, Y is —CH (C ₂ H ₅ ) CH ₂ —.

In some embodiments, X is —O—, R ³ is hydrogen, and Y is ethylene or —CH (C ₂ H ₅ ) CH ₂ —.

  Still other HDAC inhibitor compounds contemplated for use in pharmaceutical compositions, pharmacokinetic strategies, dosing regimens, methods of treatment, and combination therapies are compounds comprising a structure of formula (II) Contains an acceptable salt,

here,
X is —O—, —NR ² —, or —S (O) _n , n is 0, 1, or 2, R ² is hydrogen, —CH ₃ , —CH ₂ CH ₃ ,
Y represents ethylene, propylene, 1-methylpropylene, 2-methylpropylene, —CH (C ₂ H ₅ ) CH ₂ —, —CH (CH (CH ₃ ) ₂ ) CH ₂ —, and —CH (CH ₃ ). CH ₂ - and is,
R ³ is hydrogen, —CH ₃ , or —CH ₂ CH ₃ ;
Ar is phenyl, naphthyl, quinolinyl, benzofuranyl, or benzothienyl, where Ar is independently selected from chloro, fluoro, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, methylenedioxy, —OH Optionally substituted with one or two substituents,
R5 is trifluoromethyl, methyl, ethyl, N, N-dimethylaminomethyl, N, N-diethylaminomethyl, 2-methoxyethoxymethyl, phenoxymethyl, methoxymethyl, 3-i-propoxymethyl, morpholin-4-ylmethyl 3-hydroxypropyloxymethyl, 2-fluorophenoxymethyl, 3-fluorophenoxymethyl, 4-fluorophenoxy-methyl, 3-methoxypropyloxymethyl, pyridin-4-yloxymethyl, 2,4,6-trifluoro Phenoxymethyl, 2-oxopyridin-1-ylmethyl, 2,2,2-trifluoroethoxymethyl, 4-imidazol-1-ylphenoxymethyl, 2-phenylethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 4-Trifluo Methylpiperidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 3,3,3-trifluoropropyloxymethyl, 4-fluorophenylthiomethyl, 4-fluorophenylsulfinylmethyl, 4-fluorophenylsulfonylmethyl, pyridine -3-ylmethyloxymethyl, N-methyl-N-benzylaminomethyl, N-methyl-N-2-phenylethylaminomethyl, 3-hydroxypropylthiomethyl, 3-hydroxypropylsulfinylmethyl, 3-hydroxypropylsulfonyl -Methyl, N-methyl-N-2-indol-3-ylethylaminomethyl, 2- (4-trifluoromethylphenyl) ethyl, 2- (3-trifluoromethoxyphenyl) ethyl, N-hydroxyaminocarbonyl- Methyla Nomechiru, or 3 - (2-carboxyethyl aminomethyl).

  In some embodiments, Ar is benzofuranyl.

  In some embodiments, R5 is N, N-dimethylaminomethyl, N, N-diethylaminomethyl, pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl.

  In some embodiments, the HDAC inhibitor is selected from: N-hydroxy-4- [2- (4-methoxyquinolin-2-ylcarbonylamino) ethoxy] benzamide, N-hydroxy-4- [2S- (Trans-cinnamoylamino-butoxy] benzamide, N-hydroxy-4- [2R- (trans-cinnamoylamino-butoxy] benzamide, N-hydroxy-4- {2- [4- ( 2-methoxyethoxy) quinolin-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- [2S- (benzothiophen-2-ylcarbonylamino) butoxy] -benzamide, N-hydroxy-4- {2S- [Benzofuran-2-ylcarboni Amino] butoxy} benzamide, N-hydroxy-4- {2- [3- (methoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- {2- [3- (N, N -Dimethylaminomethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy-4- {2- [3- (i-propoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} benzamide, N-hydroxy -4- {2- [3- (3-hydroxypropoxymethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (2-methoxyethyloxymethyl) benzofuran -2-ylcarbonylamino] ethoxy} -benzamide, N-H Roxy-4- {2- [3- (pyrrolidin-1-ylmethyl) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (piperidin-1-ylmethyl) benzofuran 2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [3- (4-methylpiperazin-1-ylmethyl) benzofuran-2-ylcarbonylamino] -ethoxy} benzamide, N-hydroxy -4- {2- [5- (tetrahydropyran-4-yloxy) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hydroxy-4- {2- [5- (2-pyrrolidin-1-yl) Ethyloxy) benzofuran-2-ylcarbonylamino] ethoxy} -benzamide, N-hy Droxy-4- {2S- [5- (2-pyrrolidin-1-ylethyloxy) benzofuran-2-ylcarbonylamino] butoxy} -benzamide, N-hydroxy-4- {2- [5- (2-pyrrolidine -1-ylethyloxy) benzofuran-2-ylcarbonylamino] -1R-methyl-ethoxy} benzamide and N-hydroxy-4- {2-[(3- (benzofuran-2-yl) -4- ( Dimethylamino) -but-2-enoyl) amino] -ethoxy} benzamide, or a pharmaceutically acceptable salt thereof.

  In some embodiments, the HDAC inhibitor is selected from the HDAC inhibitors disclosed in WO 2004/092115 or WO 2005/097770, both of which are hereby incorporated by reference.

(Form and phase)
HDAC inhibitors (eg, Compound 1), including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, are in various forms, including but not limited to amorphous phase, partially crystalline form Crystal form, milled form, and nanoparticulate form. The crystalline form is known as a polymorph. Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. This arrangement can significantly affect physiochemical, formulation, and treatment parameters as well as the shelf life or stability of substances and excipients. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, visual and electrical properties, stability, and solubility. Single crystal forms dominate due to various factors such as recrystallization solvent, crystallization rate, and storage temperature. In one aspect, a crystalline form of an HDAC inhibitor (eg, Compound 1) is used in the pharmaceutical compositions described herein. In one aspect, the crystalline form of the HCl salt of Compound 1 is used in the pharmaceutical compositions described herein. In one aspect, amorphous Compound 1 is used in the pharmaceutical compositions described herein. In one aspect, the amorphous HCl salt of Compound 1 is used in the pharmaceutical compositions described herein.

(the term)
“Bioavailability” refers to the percentage by weight of an administered HDAC inhibitor (eg, Compound 1) or pharmaceutically acceptable salt that is delivered to the systemic circulation of the animal or human being studied. Total exposure of the drug when administered intravenously (AUC ( _0-∞ )) is generally defined as 100% organisms available (F%). “Oral bioavailability” refers to the absorption of an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt into the systemic circulation when the pharmaceutical composition is taken orally as compared to intravenous injection. Refers to the degree to which

“Blood plasma concentration” refers to the concentration of an HDAC inhibitor (eg, Compound 1) or pharmaceutically acceptable salt in the plasma component of the blood of a subject. Plasma concentrations of HDAC inhibitors (eg, Compound 1) or pharmaceutically acceptable salts can vary significantly from subject to subject due to variability associated with metabolism and / or interaction with other therapeutic agents. Will be understood. In one aspect, the blood plasma concentration of an HDAC inhibitor (eg, Compound 1) or pharmaceutically acceptable salt varies from subject to subject. Similarly, values such as time to reach maximum plasma concentration (C _max ) or maximum plasma concentration (T _max ), or the total area under the plasma concentration time curve (AUC ( _0-∞ )) will vary from subject to subject. . Because of this variability, in one embodiment, the amount required to constitute a “therapeutically effective amount” of an HDAC “inhibitor” (eg, Compound 1) or pharmaceutically acceptable salt is It depends on.

  An “effective plasma concentration” of an HDAC inhibitor refers to the amount of HDAC inhibitor in plasma that results in an effective exposure level for the treatment of cancer.

  “Drug absorption” or “absorption” is generally the transfer of a drug from the site of administration of the drug across the barrier to the blood vessel or site of action of the drug (eg, a drug that travels from the gastrointestinal tract to the portal vein or lymphatic system) Say the process.

  “Measurable serum concentration” or “Measurable plasma concentration” is generally measured in mg, μg, or ng of the therapeutic agent per ml, dl, or l of serum absorbed into the bloodstream after administration. Serum or plasma concentrations are described. As used herein, measurable plasma concentrations are generally measured in ng / ml or μg / ml.

  “Pharmacodynamics” refers to the factors that determine the observed biological response in relation to the concentration of drug at the site of action.

  “Pharmacokinetics” refers to the factors that determine the achievement and maintenance of an appropriate concentration of a drug at the site of action.

(Pharmaceutical composition)
In one embodiment, the oral pharmaceutical composition comprises one or more physiologically acceptable carriers (excipients and excipients) that facilitate processing the active compound into a pharmaceutically used preparation. That is, it is formulated in a conventional manner using inactive ingredients). Suitable techniques, carriers and excipients are described, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, ov), which is incorporated herein by reference in its entirety. John E., et al. Remington's Pharmaceutical Sciences, Mack Publishing Co., Remington's Pharmaceutical Sciences. , Easton, Pennsylvania 1975; A. and Lachman, L .; Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N .; Y. , 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

  The term “pharmaceutical composition” is active with other inert chemical ingredients such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, coatings, and / or excipients. It refers to a mixture with an agent (or ingredient). The pharmaceutical composition facilitates administration of the compound to a human. In one aspect, the active agent is an HDAC inhibitor (eg, Compound 1). In one embodiment, the active agent is the HCl salt of Compound 1.

  “Controlled release” as used herein refers to any release profile that is not completely immediate release.

  For oral administration, an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof, such as an HCl salt, is formulated by combining the active compound with a pharmaceutically acceptable carrier or excipient. The Such carriers allow HDAC inhibitors (eg, Compound 1) or pharmaceutically acceptable salts thereof to be formulated as tablets, powders, pills, capsules, etc. that are taken orally by the patient being treated. .

  The pharmaceutical composition comprises as active ingredients at least one pharmaceutically acceptable carrier, diluent or excipient and an HDAC inhibitor (eg Compound 1) or a pharmaceutically acceptable salt thereof. .

  In other embodiments, the pharmaceutical composition comprises, in combination with bendamustine, at least one pharmaceutically acceptable carrier, diluent, or excipient, and an HDAC inhibitor or pharmaceutically acceptable salt. .

  Oral solid dosage forms described herein are HDAC inhibitors (eg, Compound 1) that are present in crystalline form, amorphous phase, semi-crystalline form, semi-amorphous phase, or mixtures thereof. Or a pharmaceutically acceptable salt thereof.

  In one aspect, the pharmaceutical compositions disclosed herein are in the form of an oral solid dosage form. Oral solid dosage forms include tablets, pills, capsules, powders, mini-tablets, particles, beads, pellets and the like.

  The pharmaceutical compositions described herein comprise an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof and one or more of the following: (a) a binding agent, (b ) Coating, (c) disintegrant, (d) filler (diluent), (e) lubricant, (f) glidants (flow enhancers, (g) compression aids (g) compression aids), (h) colorants, (i) sweeteners, (j) preservatives, (k) suspending / dispersing agents, (l) film formers / coatings, (m) fragrances, (N) a printing ink, (o) a gelling agent, (p) a second therapeutically active agent.

  In one aspect, a pharmaceutical composition described herein comprises, in addition to an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof, one or more of the following: a) magnesium stearate, (b) lactose, (c) microcrystalline cellulose, (d) silicified microcrystalline cellulose, (e) mannitol, (f) starch (corn), (g) silicon dioxide, (h) ) Titanium dioxide, (i) stearic acid, (j) starch glycolic acid, (k) gelatin, (l) talc, (m) sucrose, (n) aspartame, (o) calcium stearate, (p) povidone, ( q) pregelatinized starch, (r) hydroxypropyl methylcellulose, (s) OPA product (coating & ink), (t) croscarmellose, (u) hydroxy B pills cellulose, (v) ethyl cellulose, (w) calcium phosphate (dibasic), (x) crospovidone, (y) shellac (and, a glaze (glaze)), (z) of sodium carbonate.

  A pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or active ingredient or pharmaceutically acceptable salt thereof in a mixture thereof, and one or more as described herein Also provided herein are pharmaceutical compositions comprising a controlled release excipient. Appropriately modified release dosage form vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separation layer coatings, enteric coatings, osmotic devices, multiparticulate devices, or combinations thereof. The pharmaceutical composition may further comprise a non-release controlling excipient.

  One or more of the active ingredients, or a combination of pharmaceutically acceptable salts, solvates, or prodrugs thereof, and a conventional tableting process to form a tablet core and then coat the core Provided herein is a pharmaceutical composition in a film-coated dosage form comprising: Tablet cores can be manufactured using conventional granulation methods, for example, wet or dry granulation, by optional comminution of the granules and subsequent compression and coating. The granulation method is described, for example, in Voigt, pages 156-69.

Excipients suitable for the production of granules are, for example, powdered fillers optionally having flow-conditioning properties, such as talc, silicon dioxide, for example Syloid® type (Grace), for example Synthetic amorphous silicic acid of SYLOID 244 FP, eg, Avicel® type (FMC), for example, AVICEL PH101, 102, 105, RC581, or RC591 type, Emcocel® Microcrystalline cellulose of the type (Mendell) or Elcema® type (Degussa); sugar, sugar alcohol, starch or starch derivatives such as lactose, dextrose, saccharose, glucose, sorbitol, mannito , Xylitol, potato starch, corn starch, rice starch, wheat starch, or carbohydrates such as amylopectin, tricalcium phosphate, calcium hydrogen phosphate, or magnesium trisilicate; gelatin, tragacanth gum, agar, alginic acid, cellulose ether, etc. Binders such as methylcellulose, carboxymethylcellulose or hydroxypropylmethylcellulose, polyethylene glycol or ethylene oxide homopolymer, in particular a degree of polymerization of approximately 2.0 × 10 ³ to 1.0 × 10 ⁵ and an approximate molecular weight of 1.0 × 10 ⁵ to 5.0 × 10 ⁶ For example, an excipient known under the name Polyox® (Union Carbide), polyvinylpyrrolidone or Are povidone, especially those having an average molecular weight of about 1000 and a degree of polymerization of about 500 to about 2500, and agar or gelatin; surfactants, eg alkyl sulfate type anionic surfactants, eg Sodium, potassium or magnesium of the alkyl ether sulfate type, n-dodecyl sulfate, n-tetradecyl sulfate, n-hexadecyl sulfate or octadecyl sulfate, for example, sodium, potassium, magnesium n- of alkanesulfonate Dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate, or n-octadecyloxyethyl sulfate, for example, fatty acid polyhydroxy alcohol ester type sodium, potassium, magnesium n- Decane sulfonate, n-tetradecane sulfonate, n-hexadecane sulfonate, or n-octadecane sulfonate, or nonionic surfactant, sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate Rate, or sorbitan monopalmitate, sorbitan tristearate or sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, With polyoxyethylene of fatty acid polyhydroxy alcohol ester such as polyoxyethylene sorbitan tristearate or polyoxyethylene sorbitan trioleate , Polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, especially ethylene oxide / propylene oxide block polymers of Pluronics® (BWC) or Synperonic® (ICI) type Such as polyethylene glycol fatty acid ester.

  Also provided herein is a pharmaceutical composition in an enteric coating dosage form, the pharmaceutical composition comprising an active ingredient or a pharmaceutically acceptable salt, solvate, or prodrug combination thereof, and an enteric coating. It contains one or more controlled release excipients used in the dosage form. The pharmaceutical composition may further comprise a non-release controlling excipient.

  In addition, the compound having an immediate release component and at least one delayed release component can be discontinuously released in the form of at least two consecutive pulses in the form of 0.5 hours up to 8 hours. A pharmaceutical composition of the dosage form is provided. The pharmaceutical composition comprises an active ingredient and one or more controlled-release excipients and non-controlled-release excipients suitable for disintegrating semipermeable membranes and also suitable as swellable substances. Contains combinations.

  Further provided herein is a pharmaceutical composition in a dosage form for oral administration to a subject, the pharmaceutical composition comprising an active ingredient or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and One or more pharmaceutically acceptable additives surrounded by an intermediate reaction layer comprising a gastric juice-resistant polymer layered material partially neutralized with alkali and having a cation exchange capacity and gastric juice-resistant outer layer. Contains a combination of form or carrier.

  Provided herein is a pharmaceutical composition comprising the active ingredient in the form of enteric coated granules as a delayed release capsule for oral administration.

  The pharmaceutical compositions as provided herein may be provided in unit dosage forms or multiple dose dosage forms. Unit dosage forms as used herein are suitable for administration to human and animal subjects and are physically packaged, individually packaged as is known in the art. It is a unit. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include individually packaged tablets and capsules. The unit dosage form may be administered in divided or multiple units thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container that are administered in separate unit dosage forms. Examples of multiple dose forms include tablet or capsule bottles.

  The pharmaceutical dosage forms can be formulated in a variety of ways to provide a variety of drug release profiles including immediate release, sustained release, and delayed release. In some cases, avoiding release of the drug after administration (ie, sustained release) until a certain time has passed, providing a substantially continuous release over a predetermined time (ie, sustained). Release) or release immediately after drug administration (ie immediate release) may be desirable.

  Oral formulations comprising an HDAC inhibitor (eg Compound 1) or a pharmaceutically acceptable salt thereof are presented in the following forms: tablets, capsules, pills, pellets, beads, granules, mixed powders. Capsules are pharmaceutically acceptable starch (eg corn, potato or tapioca starch), sugar, artificial sweeteners, powdered cellulose such as crystalline cellulose and microcrystalline cellulose, inert such as flour, gelatin, gum Containing a mixture of various fillers and / or diluents and active compounds. Tablet formulations may be made by conventional compression, wet granulation or dry granulation methods, and include pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (surfactants). Including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, silicate complex Utilizes suspending or stabilizing agents, including calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starch, and powdered sugar To do. In some embodiments, the surface modifier includes nonionic and anionic surface modifiers. For example, surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan ester, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, silicic acid Contains aluminum magnesium and triethanolamine.

  In one aspect, the oral formulations described herein use standard delayed or time release formulations to alter the absorption of the active compound.

  A binder or granulator imparts stickiness to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulators include but are not limited to starches such as corn starch, potato starch, and pregelatinized starch (eg, STARCH 1500), sugars such as gelatin, sucrose, glucose, dextrose, molasses and lactose. , Acacia, alginic acid, alginate, tochaka extract, panwar gum, ghatti gum, isabgor husks mucus, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), beegum, Natural and synthetic gums such as larcharagalactan, powdered tragacanth, and guar gum; Cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose such as hydroxypropylmethylcellulose (HPMC), AVICEL (registered trademark) -PH-101, AVICEL ( (Registered trademark) -PH-103, AVICEL (registered trademark) RC-581, AVICEL (registered trademark) -PH-105 (FMC, Marcus Hook, Pa.), And a mixture thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof including. The level of binder is from about 50% to about 99% by weight in the pharmaceutical compositions provided herein.

  Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dried starch, and powdered sugar.

  Suitable disintegrants include, but are not limited to, agar, bentonite, celluloses such as methylcellulose and carboxymethylcellulose, wood products, natural sponges, cation exchange resins, gums such as alginic acid, guar gum and Veegum HV, citrus medulla, cloth Cross-linked cellulose such as carmellose, cross-linked polymer such as crospovidone, microcrystalline cellulose such as cross-linked starch, calcium carbonate, sodium starch glycolate, polacrilin potassium, corn starch, potato starch, tapioca starch, and pregelatinized Starch, such as prepared starch, clay, aligns, and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and can be readily identified by those skilled in the art. In one aspect, the pharmaceutical compositions provided herein comprise from about 0.5% to about 15%, or from about 1% to about 5% by weight of the disintegrant.

  Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light oil, glycols such as glycerin, sorbitol, mannitol, glycerol behenate and polyethylene glycol (PEG), stearic acid, lauryl sulfate Hydrogenated vegetable oils, including sodium, talc, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, starch, lizard , Such as AEROSILR 200 (WR Grace, Baltimore, Maryland) and CAB-O-SILR (Cabot, Boston, Mass.) Or Including silica gel and mixtures thereof. In one aspect, the pharmaceutical compositions provided herein comprise from about 0.1% to about 5% by weight of the lubricant.

  Suitable glidants include colloidal silicon dioxide, CAB-O-SILR (Cabot, Boston, Mass.) And asbestos-free talc. The colorant may be any of approved and certified water-soluble and water-insoluble FD & C dyes, lake lakes, and mixtures thereof suspended in alumina hydrate. Contains. The lake pigment is a combination of absorbing a water-soluble dye with respect to a hydrated oxide of a heavy metal.

  It will be appreciated that many carriers and excipients may serve multiple functions within the same formulation.

  In further embodiments, the pharmaceutical compositions provided herein are compressed tablets, powder tablets, rapidly dissolving tablets, multiple compressed tablets, or enteric coated tablets, coated with sugar Or as a film-coated tablet.

  An enteric coating is a coating that resists the action of gastric acid but dissolves or degrades in the intestine.

  In one embodiment, the oral solid dosage forms disclosed herein include an enteric coating. The enteric coating includes one or more of the following: cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose succinate phthalate, hydroxypropyl methylcellulose acetate succinate (H Promellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate versions), styrene maleic acid copolymer, poly Methacrylic acid / acrylic acid copolymer, hydroxyethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate Over preparative tetrahydrophthalate, acrylic resin, shellac.

  An enteric coating is a coating applied to tablets, pills, capsules, pellets, beads, granules, particles, etc. so that they do not dissolve until they reach the small intestine.

  Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in hiding unwanted tastes or smells and in protecting the tablets from oxidation.

  Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Membrane coatings include, but are not limited to, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The coating of the membrane gives the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by two or more compression cycles, including layered tablets, tablets coated by compression, or tablets coated by drying.

  A tablet dosage form may be in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants, or May be prepared from the active ingredient alone, in powder, crystalline, or granular form. Flavoring and sweetening agents are particularly useful for the formation of chewable tablets and tablets and lozenges.

  The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry filled capsules (DFC), consist of two parts, one sliding over the other and thus completely surrounding the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells such as gelatin shells that are plasticized by the addition of glycerin, sorbitol, or similar polyols. Capsules may be coated as known to those skilled in the art to modify or retain dissolution of the active ingredient.

  Coloring and flavoring agents may be used in all of the above dosage forms.

  The pharmaceutical compositions provided herein are as immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, target release, and programmed release forms. It may be formulated.

  The pharmaceutical compositions provided herein are in immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, target release, and programmed release forms. It is a form.

(Controlled release)
In one aspect, the pharmaceutical compositions provided herein are in the form of a controlled release dosage form. As used herein, the term “controlled release” refers to a dosage form that, when administered orally, differs in the rate or location of release of the active ingredient from an immediate release dosage form. Controlled release dosage forms include delayed release, sustained release, extended release, sustained release, pulsed release, modified release, target release, and programmed release forms. Controlled release dosage form pharmaceutical compositions include, but are not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, and combinations thereof. Prepared using various modified release devices and methods known to those skilled in the art. The release rate of the active ingredient can also be modified by changing the particle size.

  Pharmaceutical solid oral dosage forms comprising a formulation described herein comprising an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof are HDAC inhibitors (eg, Compound 1). Or formulated to provide controlled release of a pharmaceutically acceptable salt thereof.

  In contrast to immediate release compositions, controlled release compositions allow for drug delivery to a human over an extended period of time according to a predetermined profile. Such a rate of release can provide a therapeutically effective level of drug over an extended period of time, thereby providing a longer time pharmacological response. Such long pharmacological reactions provide many inherent advantages that are not achieved with corresponding short acting immediate release preparations. In one aspect, a controlled release composition of an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof provides a therapeutically effective level of an HDAC inhibitor (eg, Compound 1) over an extended period of time. Thereby providing a longer time pharmacological response.

  In some embodiments, the solid dosage form described herein is enteric coated as a delayed release oral dosage form, i.e., to affect release in the small intestine of the gastrointestinal tract. It can be formulated as an oral dosage form of a pharmaceutical composition as described herein utilizing a melt coating. Enteric coating dosage forms are compressed or molded containing granules, powders, pellets, beads, or particles of active ingredients and / or other composition ingredients that are coated or uncoated themselves. Tablets / molds (coated or uncoated) that have been or have been extruded. In one embodiment, an enteric-coated oral dosage form is a capsule (coated or coated) containing pellets, beads, or granules of a solid carrier or composition that is itself coated or uncoated. Is not).

  The term “delayed release” as used herein refers to a generally predictable location in the gastric tube that is further distal than would have been achieved without a modified version of delayed release. It refers to delivery such that release can be achieved. In some embodiments, the method for delayed release is a coating. Any coating must be applied to a sufficient thickness so that the entire coating does not dissolve in the gastrointestinal fluid at a pH below about 5 and dissolves at a pH above about 5. In practicing the present invention to achieve delivery to the lower gastrointestinal tract, it is anticipated that any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating. In some embodiments, the polymer used in the present invention is an anionic carboxylic acid polymer. In other embodiments, the polymer and its compatible mixtures, and some of their properties, include but are not limited to.

  Shellac is also called refined rack. This coating dissolves in medium with pH> 7.

  Acrylic polymer. The ability of acrylic polymers (mainly solubility in biological fluids) can vary depending on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonia methacrylate copolymers. Eudragit® series E, L, R, S, RL, RS and NE (Rohm Pharma) are available as solubilizing in organic solvents, aqueous dispersions or dry powders is there. The Eudragit series of RL, NE, and RS are insoluble in the gastrointestinal tract, but are permeable and are used primarily when targeting the colon. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine.

  Cellulose derivative. An example of a suitable cellulose derivative is ethyl cellulose, which is a reaction mixture of phthalic anhydride and a partial acetate ester of cellulose. The ability can vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) is soluble at pH> 6. Aquateric (R) (FMC) is an aqueous based system, a spray-dried CAP pseudolatex with particles <1 [mu] m. Other ingredients in Aquateric may include pluronics tweens and acetylated monoglycerides. Other suitable cellulose derivatives are cellulose acetate trimellitate (Eastman), methylcellulose (Pharmacacoat, Methocel), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose succinate (HPMCS), and hydroxypropyl methylcellulose acetate succinate ( For example, AQOAT (Shin Etsu)) is included. The ability can vary depending on the degree and type of substitution. For example, HPMCP such as HP-50, HP-55, HP-55S, HP-55F grades are suitable. The ability can vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF) soluble at pH 5, AS-MG (MF) soluble at pH 5.5, and higher pH AS-HG (HF) is included. These polymers are provided as granules or fine powders for aqueous dispersions.

  Polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH> 5 and is not very permeable to water vapor and gastric juice.

  In some embodiments, the coating can include plasticizers and, optionally, other coating excipients such as colorants, talc, and / or magnesium stearate well known in the art. Usually contains these. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax ™ 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate , Acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers generally contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques such as spray or pan coating are used to apply the coating. The thickness of the coating must be sufficient to ensure that the oral dosage system remains intact until it reaches the desired local delivery site in the intestine.

  Coloring agents, detackifiers, surfactants, antifoaming agents, lubricants (eg, carnauba wax or PEG) are used to solubilize or disperse the coating material, and with the coating. It may be added to the coating in addition to the plasticizer to improve the coated product.

  A particularly suitable methacrylic copolymer is Eudragit L®, in particular L-30D® and Eudragit 100-55®, manufactured by Rohm Pharma, Germany. In Eudragit L-30D®, the ratio of free carboxyl groups to ester groups is approximately 1: 1. Furthermore, the copolymer is insoluble in gastrointestinal fluids having a pH below 5.5, generally a pH of 1.5-5.5 (ie, the pH present in body fluids of the upper gastrointestinal tract), It is known to dissolve easily or partially at pH above 0.5 (ie, the pH value present in the small intestine).

  In some embodiments, the material includes shellac, acrylic polymer, cellulose derivative, polyvinyl acetate phthalate, and mixtures thereof. In other embodiments, the material is Eudragit® series E, L, RL, RS, NE, L, L300, S, 100-55, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, Contains hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, and Coteric.

  For some types of drugs, it is desirable to release the drug in a “pulse”, where a single dosage form gives an initial dose of drug followed by a non-release rest period, after which a second dose of drug The dose is released, followed by one or more further non-release pauses and drug release “pulses”. Alternatively, no drug is released for a period of time after administration of the dosage form, after which a single dose of drug is released, followed by a rest period that does not release one or more additional drugs and a drug release “pulse”. Continue.

  Pulsed drug delivery, for example, to have an active agent that has a short half-life and is administered two or three times a day, an active agent that is metabolized extensively throughout the body, and an optimal pharmacodynamic effect Useful with active agents that must maintain specific plasma levels.

  A pulsed dosage form can provide one or more immediate release pulses at a predetermined time after a controlled delay time or at a particular site. Pulse dosage forms comprising the formulations described herein comprising an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof are administered using the various pulse formulations that have been described. For example, such formulations include, but are not limited to, US Pat. Nos. 5,011,692, 5,017,381, 5,229,135, 5,840,329, 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441, and 5,837,284. In one embodiment, the controlled release dosage form is a pulsed release solid oral dosage form comprising at least two particle groups (ie, multiparticulates) each containing a formulation described herein. The first group of particles provides a substantially immediate dosage of an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt thereof after ingestion by a mammal. The first particles can be uncoated or can include a coating and / or sealant. The second group of particles comprises coated particles and is mixed with one or more binders in the formulation to provide a total administration of an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt. About 2% to about 75%, preferably about 2.5% to about 70%, and more preferably about 40% to about 70% by weight of the amount. The coating includes a sufficient amount of a pharmaceutically acceptable ingredient to provide a delay of about 2-7 hours after digestion before releasing the second dose. Suitable coatings are, by way of example only, acrylic resins (eg, Eudragit® EPO, Eudragit® L30D-55, Eudragit®), alone or mixed with a cellulose derivative (eg, ethylcellulose). FS 30D, Eudragit (registered trademark) L100-55, Eudragit (registered trademark) L100, Eudragit (registered trademark) S100, Eudragit (registered trademark) RD100, Eudragit (registered trademark) E100, Eudragit (registered trademark) L12.5, Eudragit PH sensitive coating (enteric coating) such as (registered trademark) S12.5 and Eudragit (registered trademark) NE30D (Eudragit (registered trademark) NE 40D)) or HD One or more differently degradable, such as non-enteric coatings with various thicknesses to provide different release of formulations comprising a C inhibitor (eg Compound 1) or a pharmaceutically acceptable salt thereof Includes coating.

(Multi-particle controlled release device)
In some embodiments, the pharmaceutical compositions described herein are multiparticulate controlled release devices. The multiparticulate controlled release device comprises a number of particles, granules or pellets ranging from about 10 μm to about 3 mm in diameter, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. Such multiparticulates are made by wet granulation, dry granulation, extrusion / spheronization, roller compaction, melt coagulation, seed core spray coating, and combinations thereof. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

  Other excipients or carriers as described herein are blended with the pharmaceutical composition to assist in processing and forming the multiparticulates. The resulting particles may themselves constitute a multiparticulate device or may be coated with various film forming materials such as enteric polymers, water swells, water soluble polymers, and the like. Multiparticulates can be further processed as capsules or tablets.

  Enteroprotective drug absorption system (IPDAS) is a multiparticulate tablet technology consisting of high density controlled release beads that are compressed into tablet form. The beads can be produced by techniques such as extrusion spheronization and controlled release can be achieved using different polymer systems to coat the resulting beads. Alternatively, the drug can also be coated on an inert carrier such as non-pareil seed to produce immediate release multiparticulates. Controlled release can be achieved by forming a polymer film on these immediate release multiparticulates. When an IPDAS tablet is ingested, it disintegrates rapidly, dispersing the drug-containing beads in the stomach. The beads then enter the duodenum and travel along the gastrointestinal tract in a controlled and stepwise manner, regardless of the fed state. Release of the active ingredient from the multiparticulates occurs via a process of dispersion through either the polymer membrane and / or the polymer / active ingredient micromatrix formed in the extruded / spheronized multiparticulates. The intestinal protection of IPDAS is thanks to the multiparticulate nature of the formulation that ensures wide dispersion of the drug throughout the gastrointestinal tract.

  The Spheroid Oral Absorption System (SODAS) is a multiparticulate technology that allows the manufacture of customized dosage forms and responds directly to the needs of individual drug candidates. It can provide a number of specifically tailored drug release profiles including immediate release of drug and subsequent sustained release to produce a rapid onset of action that lasts for at least 12 hours. Alternatively, the opposite scenario can be achieved that delays drug release for several hours.

  A programmable oral drug absorption system (PRODAS) is presented as a number of mini-tablets contained in hard gelatin capsules. Hence, it combines the advantages of tableting technology within the capsule. Many different mini-tablets can be incorporated, each mini-tablet formulated separately and programmed to release the drug at different sites within the gastrointestinal tract. These combinations can include immediate release, delayed release, and / or controlled release mini-tablets. It is also possible to incorporate mini-tablets of different sizes for high drug loading. Its size is usually in the range of 1.5 to 4 mm in diameter.

Many other types of controlled release systems known to those skilled in the art are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic acid, polyglycolic acid, polyanhydrides, polycaprolactone; lipids or mono-, di- and triglycerides containing sterols such as cholesterol, cholesterol esters and fatty acids Non-polymer-based systems with porous matrices that are lipids containing neutral fats such as; hydrogel release systems; silastic systems; peptide-based systems; wax coatings using conventional binders, biodegradable dosage forms, compressed tablets, etc. Is mentioned. For example, Liberman et al. , Pharmaceutical Dosage Forms, 2 Ed. , Vol. 1, pp. 209-214 (1990); Singh et al. , Encyclopedia of pharmaceutical Technology, 2 ^nd Ed. , Pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, See 6465014 and 69329983.

(Matrix controlled release device)
In some embodiments, the pharmaceutical compositions provided herein are modified release dosage forms made using matrix controlled release devices known to those skilled in the art (Takadora et al, “Encyclopedia of Controlled”). Drug Delivery, "Vol. 2, Mathiowitz ed., Wiley, 1999).

  In one embodiment, the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device. The modified release dosage form is a water swellable, erodible, or soluble polymer. Water swellable, erodible, or soluble polymers include synthetic polymers such as polysaccharides and proteins, naturally occurring polymers, and derivatives thereof.

  Materials useful for forming the erodible matrix include chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, caraya gum, locust bean gum, gum tragacanth, carrageenan, gati gum, guar gum, xanthan gum, and scleroglucan; Starches such as maltodextrin; hydrocolloids such as pectin; phospholipids such as lecithin; alginate; propylene glycol alginate; gelatin; collagen; and ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxy Ethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose Cellulose derivatives such as butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), and ethylhydroxyethylcellulose (EHEC) Polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid ester; polyacrylamide; polyacrylic acid; ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); (2-hydroxyethyl methacrylate); polylactide; co-weight of L-glutamic acid and ethyl-L-glutamate Degradable lactic acid-glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and homopolymer and butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, And other acrylic acid derivatives such as, but not limited to, a copolymer of (trimethylaminoethyl) methacrylate chloride.

  In some embodiments, the pharmaceutical composition is formulated in a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and is released primarily by dispersion through the inert matrix once administered. Materials suitable for use as non-erodible matrix devices include polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate Copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / Vinyl alcohol copolymer, vinyl chloride copolymer having ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, polyvinyl chloride Insoluble plastics such as plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer; and hydrophilic such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate And aliphatic polymers such as, but not limited to, carnauba wax, microcrystalline wax, and triglycerides.

  In a matrix controlled release system, the desired polymer type, polymer viscosity, polymer and / or active ingredient particle size, ratio of active ingredient to polymer, and other excipients or carriers in the composition may be Release kinetics can be controlled.

In one aspect, the modified release dosage form is prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation, followed by compression, melt granulation, and subsequent compression.

  In some embodiments, the matrix controlled release system includes an enteric coating so that no drug is released in the stomach.

(Permeability controlled release device)
In some embodiments, the pharmaceutical compositions provided herein in a modified release dosage form are made using an osmotic controlled release device. The osmotic controlled release device includes a one-chamber system, a two-chamber system, an asymmetric membrane technology (AMT), and an extruded core system (ECS). In general, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane with at least one delivery port that encloses the core. The semipermeable membrane causes drug release through the delivery port by extrusion by controlling the inflow of water from the aqueous environment used to the core.

  In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent. The osmotic agent generates a driving force for transporting water from the environment in which it is used into the core of the device. One class of water swellable hydrophilic polymers of osmotic agents, also called “osmopolymers” or “hydrogels”, includes hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol ( PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid, poly (methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP co-weight PVA / PVP copolymers with hydrophobic monomers such as coalesced methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (H C), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate, It is not limited to these.

  Another class of osmotic agents are osmogens. The osmogen can absorb water to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens are inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; dextrose, fructose Sugars such as glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edet Examples include, but are not limited to, organic acids such as acids, glutamic acid, p-toluenesulfonic acid, succinic acid, tartaric acid; urea; and mixtures thereof.

  Osmotic agents with different dissolution rates can be used to affect how quickly the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as Mannomeme EZ (SPI Pharma, Lewes, DE) provide faster delivery for the first few hours to produce the desired therapeutic effect quickly, over long periods of time. It can be used to provide a gradual and continuous release of the remaining amount to maintain a desired level of therapeutic or prophylactic effect. In this case, the active ingredient is released at a rate that replaces the metabolized and excreted amount of the active ingredient.

  The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

  Materials useful for the formation of semipermeable membranes are various grades of acrylic, vinyl, ether that have water permeability and water insolubility at physiologically relevant pH, or become water insoluble by chemical changes such as crosslinking. , Polyamides, polyesters, and cellulose derivatives. Examples of suitable polymers useful for forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionic acid, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinic acid, cellulose acetate trimellitate (CAT), CA dimethylamino acetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA Triacetate of p-toluenesulfonic acid, agar acetate, amylose triacetate, β-glucan acetate, β-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum , Hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acid and ester and poly -(Methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyether, polysulfone, polyethersulfone, polystyrene, polyvinyl halide, polyvinyl ester and ether, natural wax, Synthetic waxes may be mentioned.

  The semipermeable membrane may be a hydrophobic microporous membrane. Here, the pores are substantially filled with gas and not wetted by an aqueous medium, as disclosed in US Pat. No. 5,798,119, but are permeable to water vapor. Such hydrophobic but water vapor permeable membranes are typically polyalkenes, polyethylenes, polypropylenes, polytetrafluoroethylenes, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, It consists of hydrophobic polymers such as polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

  The semipermeable membrane delivery port may be formed after coating by mechanical or laser drilling. The delivery port may also be formed in situ by erosion of a plug of water soluble material or by rupturing a thinner portion of the membrane over the core recess. In addition, the delivery port may be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in US Pat. Nos. 5,612,059 and 5,698,220.

  The total amount of active ingredient released and the rate of release can be substantially adjusted by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of delivery ports.

  The osmotic controlled release dosage form pharmaceutical composition may further comprise additional conventional excipients or carriers as described herein to facilitate the performance or processing of the formulation.

  Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (Remington: The Science and Practice of Pharmacia; Santus and Baker, J. Controlled Release 1995, 35, 1- 21; Verma et al., Drug Development and Industrial Pharmacology 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

  In other embodiments, the pharmaceutical compositions provided herein are formulated as an AMT controlled release dosage form. The AMT controlled release dosage form comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient and other pharmaceutically acceptable excipients or carriers. See US Pat. No. 5,612,059 and International Patent Application Publication No. 2000/17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation methods, and dip coating methods.

  In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms. The ESC controlled release dosage form includes an osmotic membrane that coats a core comprising an active ingredient, hydroxylethylcellulose, and other pharmaceutically acceptable excipients or carriers.

(Multilayer tablet)
In one aspect, the controlled release formulation is in the form of a multilayer tablet. Multilayer tablets include an inert core onto which a layered drug (and optional excipients) is applied, followed by an enteric coating. A second layer of drug is applied over the first enteric coating, followed by a second enteric coating over the second layer of drug. The enteric coating should ensure that the release of drug from each layer is separated in time by at least 3-6 hours.

(Immediate release)
In some embodiments, a pharmaceutical composition provided herein in an immediate release dosage form is a therapeutically effective ingredient or a combination thereof as described in USP XXII, 1990 (The United States Pharmacopeia.). Release at least 75% of the combination and / or meet the disintegration or dissolution requirements of the immediate release tablet of the particular therapeutic agent or combination thereof contained in the tablet core. Immediate release pharmaceutical compositions include capsules, tablets, oral solutions, powders, beads, pellets, particles, etc.

(Parenteral administration)
In some embodiments, the pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or transplantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, And subcutaneous administration.

  In other embodiments, the pharmaceutical compositions provided herein can be formulated in any dosage form. The optional dosage forms are suitable for parenteral administration including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid dosage forms suitable for liquid solutions or suspensions prior to injection. Yes. Such dosage forms can be prepared according to conventional methods known to those skilled in the pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).

  A pharmaceutical composition intended for parenteral administration may comprise one or more pharmaceutically acceptable carriers and excipients. The carrier and excipient include an aqueous vehicle, a water-miscible vehicle, a non-aqueous vehicle, an antibacterial or antiseptic agent against microorganism growth, a stabilizer, a dissolution accelerator, an isotonic agent, a buffer, an antioxidant, Local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, dissolution protectants, thickeners, pH adjusters, and inert gases. However, it is not limited to these.

  Suitable aqueous vehicles include water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. However, it is not limited to these. Non-aqueous vehicles include plant-derived fixed oil, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and palm oil. Examples include, but are not limited to, chain triglycerides and coconut seed oil. Water miscible vehicles include ethanol, 1,3-butanediol, liquid polyethylene glycol (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide. However, it is not limited to these.

  Suitable antibacterial or preservatives include phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propyl-paraben, and sorbine Examples include, but are not limited to acids. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein including bisulfite and sodium metabisulfite. Suitable local anesthetics include but are not limited to procaine hydrochloride. Suitable suspending and dispersing agents are those described herein including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL® CyDex Cyclodextrins including, but not limited to, Lenexa, KS).

  In some embodiments, the pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. Single dose formulations are packaged in ampoules, vials or syringes. Multi-dose parenteral preparations should contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. As is known and practiced in the art, all parenteral formulations must be sterile.

  In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product comprising a lyophilized powder and a subcutaneous injection tablet that is reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product that is reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

(Pharmacokinetic analysis)
In one embodiment, any standard pharmacokinetic protocol determines a plasma concentration profile in a human after administration of a formulation described herein comprising an HDAC inhibitor (eg, Compound 1), thereby The formulation is used to establish whether it meets the pharmacokinetic and pharmacodynamic criteria described herein. For example, a randomized single dose crossover study is performed using a group of healthy adult human subjects. Smaller groups are sufficient for specific purposes, but the number of subjects should be sufficient to adequately control the statistical analysis variability, typically about 10 or more. Each subject receives a single dose (eg, a dose comprising about 10 mg to about 300 mg of Compound 1) at time zero. Blood samples are collected from each subject prior to administration (eg, 15 minutes before) and at several intervals after administration. In a particular example, several samples are taken within the first hour and then less frequently. Illustratively, blood samples are collected at 0 (pre-dose), 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 16 hours after administration. If the same subject is used for the study of the second test formulation, a period of at least 10 days must elapse before administration of the second formulation. The plasma is separated from the blood sample by centrifugation, and the separated plasma is treated with a validated high performance liquid chromatography / tandem mass spectrometry (eg, LC-MS / MS, LC / APCI-MS / MS) treatment, such as , Ramu et al, Journal of F Chromatography B, 751 (2001) 49-59, etc., and analyzed for HDAC inhibitors (eg, Compound 1).

  Any formulation that provides the desired pharmacokinetic profile and pharmacodynamic effect is suitable for administration by this method.

(Medication and treatment regimen)
In one embodiment, the composition comprising an HDAC inhibitor (eg, Compound 1) described herein is in an amount sufficient to partially block at least one of the cancer symptoms. Is administered to a human having Effective amounts for this use depend on the severity and course of the cancer, previous treatment, patient health, weight, and response to the drug, and / or the judgment of the treating physician.

  In some embodiments, administration of a compound, composition, or treatment as described herein includes chronic administration. In certain embodiments, chronic administration is utilized in certain cases where the patient's condition does not improve and / or based on the physician's discretion. In certain embodiments, chronic administration includes long-term administration, including, for example, over the life of another patient, to ameliorate cancer symptoms and otherwise control cancer symptoms.

  In some embodiments, administration of a compound, composition, or treatment described herein is given sequentially.

  In some aspects, administration of the administered drug is temporarily interrupted for a period of time (ie, a “drug holiday”). The length of the drug holiday varies between 4 and 9 days.

In one aspect, a pharmaceutical composition comprising an HDAC inhibitor (eg, Compound 1) comprises continuous daily administration of an HDAC inhibitor (eg, Compound 1), followed by non-daily administration of an HDAC inhibitor (eg, Compound 1). It is administered to humans with cancer in a cycle that includes administration. Such a dosing schedule for HDAC inhibitors (eg, Compound 1) is to achieve a pharmacodynamic response to HDAC inhibitors (eg, Compound 1) while limiting the incidence of Grade 4 thrombocytopenia. to enable. Grade 4 thrombocytopenia typically includes cases where the number of human platelets is less than 25000 per mm ² . In one aspect, a pharmaceutical composition comprising an HDAC inhibitor (eg, Compound 1) comprises 5, 6, 7, 8, or 9 consecutive daily administrations of HDAC inhibitor (eg, Compound 1) followed by HDAC inhibition. Administered to a human with cancer in a cycle that includes 5, 6, 7, 8, or 9 consecutive non-administrations of the agent (eg, Compound 1).

  If a human is receiving a combination therapy with a second drug other than an HDAC inhibitor (eg, Compound 1), treatment with the second drug may be performed on the day when the HDAC inhibitor (eg, Compound 1) is not administered. Will not be canceled. In one aspect, when a human is receiving a combination therapy with a second drug other than an HDAC inhibitor (eg, Compound 1), treatment with the second drug is such that the HDAC inhibitor (eg, Compound 1) is Discontinue on non-administered days.

  In one aspect, an immediate release formulation of an HDAC inhibitor (eg, Compound 1) is administered to a human twice daily. In one aspect, an immediate release formulation of an HDAC inhibitor (eg, Compound 1) is administered to a human twice a day, and the two immediate release doses are administered about 3 hours to about 6 hours apart.

  In one aspect, a controlled release formulation of an HDAC inhibitor (eg, Compound 1) is administered to a human once a day. In one aspect, a controlled release formulation of an HDAC inhibitor (eg, Compound 1) administered to a human once daily is derived from daily administration of two immediate release formulations of an HDAC inhibitor (eg, Compound 1). The same amount of HDAC inhibitor (eg, Compound 1) that would be provided is provided. In one aspect, a controlled release formulation of an HDAC inhibitor (eg, Compound 1) administered to a human once daily is derived from daily administration of two immediate release formulations of an HDAC inhibitor (eg, Compound 1). Provides the same amount of HDAC inhibitor (eg, Compound 1) that would be administered, wherein the two immediate release doses are administered about 3 to about 6 hours apart.

(Daily amount)
In certain embodiments, by way of example only, an HDAC inhibitor (eg, Compound 1) or a pharmaceutically acceptable salt of an HDAC inhibitor (eg, Compound 1) in combination with an alkylating agent such as bendamustine that is administered. The amount of can vary depending on factors including, but not limited to, the type of formulation utilized, the type and severity of the cancer, the human ID (eg, body weight, age), and / or the route of administration. . In various embodiments, the desired dose is a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, eg, as 2, 3, 4 or more sub-doses per day. Presented conveniently.

  In one embodiment, the HDAC inhibitor is administered as shown herein in some embodiments in combination with bendamustine administered via intravenous injection. In one embodiment, the HDAC inhibitor is administered as shown herein in combination with bendamustine administered on days 1 and 2 of a 21 day treatment cycle.

  In some embodiments, the pharmaceutical compositions described herein are in unit dosage forms suitable for administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof. In one embodiment, the unit dosage form is in the form of a package containing discrete amounts of the formulation. Non-limiting examples are tablets or capsules packed in vials or ampoules, and powders. In one embodiment, the aqueous suspension composition is packaged in a single dose non-resealable container. Alternatively, multiple dose resealable containers are used. In that case, it typically contains a preservative in the composition.

The daily amount of Compound 1, or a pharmaceutically acceptable salt thereof, administered to a human ranges from about 10 mg / mm ² to about 200 mg / mm ² . In one aspect, the daily amount of Compound 1 or a pharmaceutically acceptable salt thereof administered to a human ranges from about 30 mg / mm ² to about 90 mg / mm ² . In one embodiment, the amount of daily Compound 1, or a pharmaceutically acceptable salt thereof to be administered to humans, about 20 mg / mm ^2, about 30 mg / mm ^2, about 40 mg / mm ^2, about 50 mg / mm ² , about 60 mg / mm ² , about 70 mg / mm ² , about 80 mg / mm ² , or about 90 mg / mm ² .

In one aspect, Compound 1, or a pharmaceutically acceptable salt thereof, is about 20 mg / mm ² , about 30 mg / mm ² , about 40 mg / mm ² , about 50 mg / mm ² , about 60 mg / mm ² , about 70 mg. / Mm ² , about 80 mg / mm ² , or about 90 mg / mm ² of Compound 1 as an immediate release formulation. In one aspect, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as an immediate release formulation comprising about 30 mg / mm ² of Compound 1, or a pharmaceutically acceptable salt thereof.

  In one aspect, the HDAC inhibitor (eg, Compound 1) is administered as two immediate release formulations, wherein the second immediate release formulation is about 4 hours to about 6 after the first dose is administered. Administer after hours. Each immediate release formulation includes the same amount of an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, as described herein. Two immediate release formulations provide sustained effective plasma levels of HDAC inhibitors (eg, Compound 1) required for therapeutic and pharmacodynamic effects with minimal side effects. In one aspect, sustained effective plasma levels of an HDAC inhibitor (eg, Compound 1) are maintained from about 6 hours to about 8 hours.

In one aspect, Compound 1, or a pharmaceutically acceptable salt thereof, is about 30 mg / mm ² , about 40 mg / mm ² , about 50 mg / mm ² , about 60 mg / mm ² , about 70 mg / mm ² , about 80 mg. / Mm ² , or as a controlled release formulation containing about 90 mg / mm ² of Compound 1. In one aspect, Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a controlled release formulation comprising about 60 mg / mm ² of Compound 1, or a pharmaceutically acceptable salt thereof.

  In one aspect, the immediate release formulation comprises from about 10 mg to about 300 mg of Compound 1. In one aspect, the immediate release formulation comprises from about 20 mg to about 200 mg of Compound 1.

  In one aspect, the controlled release formulation comprises from about 20 mg to about 600 mg of Compound 1. In one aspect, the immediate release formulation comprises from about 40 mg to about 400 mg of Compound 1.

(cancer)
In one aspect, an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, is used for the treatment of cancer in humans. In one aspect, an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, is used for the treatment of blood cancer in humans. In one aspect, an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, is used for the treatment of solid tumors in humans.

  Hematological cancers include blood or bone marrow cancers such as leukemia or lymphoma.

  Lymphoma is a cancer that begins in cells of the immune system. There are two basic categories of lymphoma. One type is Hodgkin lymphoma characterized by the presence of a type of cell called Reed-Stamberg cells. The other category is non-Hodgkin lymphoma, which includes a large and diverse group of cancers of immune system cells. Non-Hodgkin's lymphoma can be further divided into cancers that have a late (slow growth) course and an aggressive (fast growth) course.

  Leukemia is a cancer that begins in blood-forming tissues such as bone marrow, produces a large number of blood cells, and enters the blood cells into the bloodstream.

  In one aspect, the cancer is a solid tumor or a lymphoma or leukemia. In one aspect, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, germ cell tumor, blast tumor, or blastoma.

  In one aspect, an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, is used for the treatment of a cancer selected from: Heart: Sarcoma (angiosarcoma, fibrosarcoma, rhabdomitis) Myoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveoli (bronchi) ) Cancer, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (Duct adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine ( Adenocarcinoma, tubular adenoma, chorionic gland Urogenital tract: kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (glandular) Cancer, sarcoma), testis (seminal epithelioma, teratoma, embryonal cancer, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver cancer (liver) Cell carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (Reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochronoma), benign chondroma, chondroblastoma, chondromyxiofibroma, Osteoid osteoma and giant cell tumor; nervous system: head Bone (osteoma, hemangioma, granuloma, xanthoma, osteoarthritis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma) , Ependymoma, germinoma [pineoblastoma], glioblastoma multiforme, oligodendron, schwannoma, retinoblastoma, congenital tumor), spinal cord (neurofibroma, meningioma, nerve) Gliomas, sarcomas); gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma) Endometrioid tumor, glioblastoma, clear cell carcinoma, unclassified cancer], granulosa-capsular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma, vulva (squamous epithelium) Cancer, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape sarcoma [fetal rhabdomyosarcoma], fallopian tube (carcinoma); hematology: blood (bone marrow Leukemia [acute And chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hodgkin disease, non-Hodgkin lymphoma [malignant lymphoma], skin: malignant melanoma, basal Cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, mole, dysplastic nevi, lipoma, hemangioma, dermal fibroma, keloid, psoriasis; adrenal gland: neuroblastoma; gallbladder cancer.

  In one aspect, the cancer is breast cancer, colon cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer , Germ cell tumor, mast cell tumor, neuroblastoma, mastocytosis, testicular cancer, glioblastoma, astrocytoma, lymphoma, melanoma, myeloma, acute myeloid leukemia (AML), acute lymphocytic leukemia ( ALL), myelodysplastic syndrome, and chronic myelogenous leukemia (CML).

  In one aspect, the cancer is lymphoma. In one aspect, the lymphoma is a B cell lymphoma, a T cell lymphoma, a Hodgkin lymphoma, or a non-Hodgkin lymphoma.

  In one aspect, the cancer is T cell lymphoma or leukemia.

  In one aspect, the T-cell lymphoma is a peripheral T cell lymphoma. In another aspect, the T cell lymphoma or leukemia is T cell lymphoblastic leukemia / lymphoma. In yet another aspect, the T cell lymphoma is a cutaneous T cell lymphoma. In another aspect, the T cell lymphoma is an adult T cell lymphoma. In one aspect, the T-cell lymphoma is peripheral T cell lymphoma, lymphoblastic lymphoma, cutaneous T cell lymphoma, NK / T cell lymphoma, or adult T cell leukemia / lymphoma.

  In one embodiment, the cancer is sarcoma. Sarcomas are cancers that start in muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. Sarcomas include any one of the following: alveolar soft tissue sarcoma, angiosarcoma, sex skin, desmoid tumor, fibrogenic small round cell tumor, extraosseous chondrosarcoma, extraosseous osteosarcoma, fibrosarcoma, blood vessel Peripheral cell tumor, angiosarcoma, Kaposi sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, malignant fibrous histiocytoma, neurofibrosarcoma, malignant peripheral nerve sheath tumor (MPNST), rhabdomyosarcoma, synovial sarcoma, Askin tumor, Ewing tumor, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, chondrosarcoma.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of soft tissue sarcomas in humans.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of adult syndrome (MDS) in humans.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of chronic myeloid leukemia (CML) in humans.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of non-Hodgkin lymphoma in humans. In one aspect, an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, is used for the treatment of Hodgkin's disease in humans.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of multiple myeloma in humans.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of chronic lymphocytic leukemia. In one aspect, an HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, is used for the treatment of acute lymphocytic leukemia.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of solid tumors in humans.

  In one aspect, the HDAC inhibitor (eg, Compound 1), or a pharmaceutically acceptable salt thereof, and in some embodiments, an HDAC inhibitor (eg, Compound 1), or a combination thereof, in combination with bendamustine. Pharmaceutically acceptable salts are used for the treatment of sarcomas in humans.

(Further combination therapy)
In one embodiment, the compositions and methods described herein are also used in combination with other therapeutic reagents selected for specific utility against the cancer being treated. In general, the compositions described herein, and other agents in embodiments in which combination therapy is used, need not be administered in the same pharmaceutical composition, but have different physical and chemical properties, and thus different routes. Is administered. In one embodiment, the initial administration is performed according to established protocols and then further modified based on the observed effects, dosage, mode of administration and number of administrations.

  In certain embodiments, the particular choice of compound used will depend on the attending physician's diagnosis, the attending physician's judgment of the patient's condition, and the appropriate treatment protocol. In various embodiments, depending on the nature of the cancer, the patient's condition, and the actual choice of the compound used, the compounds can be either together (eg, simultaneously, essentially simultaneously, or within the same treatment protocol) or It is administered continuously. In certain embodiments, the determination of the order of administration of each therapeutic agent and the number of repetitions of administration in a treatment protocol is based on an assessment of the disease being treated and the condition of the patient.

  In one embodiment, it is understood that the dosing regimen for treating cancer will vary depending on various factors. These factors include the type of cancer the person is suffering from, as well as the age, weight, sex, diet, and medical condition of the person. Thus, in one embodiment, the dosing regimen actually deviates from the dosing regimens described herein, as the dosing regimen actually used varies greatly. In certain embodiments, treatment of cancer with a combination of an HDAC inhibitor (eg, Compound 1) and an additional agent reduces the effective amount of the HDAC inhibitor (eg, Compound 1) and / or the second agent. Can do.

  The formulations described herein are administered and dosed according to good medical practice, taking into account the individual patient's clinical condition, method of administration, dosing schedule, and other factors known to the physician.

  A contemplated pharmaceutical composition provides a therapeutically effective amount of an HDAC inhibitor (eg, Compound 1) that allows administration, eg, once daily, twice daily, three times daily. In one aspect, the pharmaceutical composition provides an effective amount of an HDAC inhibitor (eg, Compound 1) that allows for once daily dosing.

  In certain instances, it is appropriate to administer an HDAC inhibitor (eg, Compound 1) in combination with another therapeutic agent.

  In certain embodiments, the therapeutic efficacy of an HDAC inhibitor (eg, Compound 1) is an adjuvant (ie, the adjuvant itself has minimal therapeutic benefit, but in combination with another therapeutic agent). Increased by administration), which increases the overall therapeutic benefit to the patient. In some embodiments, the benefit enjoyed by the patient is increased by administering an HDAC inhibitor (eg, Compound 1) with another therapeutic agent (including a therapeutic regimen) that has a therapeutic benefit. In certain embodiments, in the treatment of cancer involving the administration of an HDAC inhibitor (eg, Compound 1), providing the patient with other therapeutic agents or therapies for cancer also results in increased therapeutic benefit. In various embodiments, administration of an HDAC inhibitor (eg, Compound 1) in combination with a second agent to an individual provides the individual with, for example, an additive or synergistic benefit.

When the drug is used in combination therapy, the therapeutically effective amount will vary. Determination of therapeutically effective amounts of drugs and other agents when used in a combination treatment regimen is accomplished in any manner. For example, the use of metronome administration, i.e., providing lower doses more frequently to minimize toxic side effects, can be utilized. In certain instances, the combination therapy reduces the therapeutically effective amount of HDAC less than would be obtained when administering either an HDAC inhibitor (eg, Compound 1) and a second agent alone. Either or both of the inhibitor (eg, Compound 1) and the second agent can have.

  Combination therapy regimens include, as a non-limiting example, administration of an HDAC inhibitor (eg, Compound 1) is initiated before, during, or after treatment with a second agent, using a second agent A therapeutic regimen that continues until any time during treatment or until the end of treatment with the second agent. It may also be administered simultaneously with an HDAC inhibitor (eg, Compound 1) and a second agent used in combination, or at intervals that decrease or increase at different times and / or during the treatment period. Including treatment. Combination therapy further includes periodic treatments that start and stop at various times to assist the clinical management of the patient.

  In either case, the plurality of therapeutic agents (one of which is an HDAC inhibitor (eg, Compound 1)) is administered in any order, including, for example, simultaneously. When administration is simultaneous, the multiple therapeutic agents are, in various embodiments, in a single and unified form, or in multiple forms (eg, as a single pill or as two separate pills). Provided. In various embodiments, one of the therapeutic agents is given in multiple doses, or both are given as multiple doses. In certain embodiments where administration of multiple agents is not simultaneous, the timing between the administration of multiple agents is any acceptable range including, for example, a range greater than 0 weeks and less than 4 weeks. In some embodiments, the combination methods, compositions and formulations comprise an HDAC inhibitor (eg, Compound 1), a second agent, and a third agent. In further embodiments, additional agents are also utilized.

  In certain embodiments, the initial administration is via oral administration such as, for example, pills, capsules, tablets, solutions, suspensions, etc., or combinations thereof. In certain embodiments, the HDAC inhibitor (eg, Compound 1) is administered as soon as it becomes feasible after the onset of cancer is detected or suspected, and is administered for a period of time necessary for the treatment of cancer. Is done. In certain embodiments, an agent, formulation or composition described herein is for the treatment of cancer, including, as a non-limiting example, a period of at least 2 weeks, at least 1 month, or longer than 1 month. For as long as necessary.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with at least one additional therapeutic agent selected from: a DNA damaging agent; a topoisomerase I or II inhibitor; alkyl PARP inhibitor; proteasome inhibitor; RNA / DNA antimetabolite; antimitotic agent; immunomodulator; anti-angiogenic agent; aromatase inhibitor; hormone regulator; apoptosis inducer; Antibody; abarelix; ABT-888; aldesleukin; aldesleukin; alemtuzumab; alitretinoin; allopurinamine; altretamine; amifostine anastrozole; asparaginase; azacitidine; AZD-2281; bendamustine; alomide); chloroquine; bevacizumab; bexarotene; bleomycin; bortezomib; BSI-201; busulfan; busulfan; carsterone; capecitabine; carboplatin; Cytarabine; cytarabine liposome; dacarbazine; dactinomycin; darbepoetin alfa; dasatinib; daunorubicin liposome; daunorubicin; decitabine; denileukine; dexrazoxane; Erlotinib; estramustine; etoposide phosphate; etoposide; exemestane; filgrastim; floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib; gemcitabine; gemtuzumab ozogamicin; goserelin acetate; Ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; interferon alfa 2a; interferon alfa-2b; irinotecan; lenalidomide; letrozole; leucovorin; leuprolide acetate; levamisole; lomustine; Purine; methotrexate; methoxalene; mitomycin C; mitomycin C; mitotane; Nandrolone phenylpropionate; nelarabine; NPI-0052; nofetumomab; oprelbequin; oxaliplatin; paclitaxel; paclitaxel protein-binding particles; palifermin; Grastim; pemetrexedoni sodium; pentostatin; pipbroman; pricamycin; mitramycin; sodium porfimer; procarbazine; quinacrine; RAD001; rasburicase; rituximab; Teni Sid; testolactone; thalidomide; thioguanine; thiotepa; topotecan; toremifene; tositumomab; tositumomab / I-131 tositumomab; Trastuzumab; tretinoin; uracil mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; zoledronate; and zoledronic acid. In certain embodiments, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with bendamustine and rituximab. In certain embodiments, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with bendamustine and rituximab.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with a topoisomerase inhibitor, a tubulin interactor, a DNA interacting agent, a DNA alkylating agent, and / or a platinum complex.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with an oxaliplatin, tyrosine kinase inhibitor, irinotecan (CPT-11), azacitidine, fludarabine, or bendamustine.

  Examples of tyrosine kinase inhibitors include erlotinib, gefitinib, lapatinib, vandetanib, neratinib, lapatinib, neratinib, axitinib, sunitinib, sorafenib, restaurtinib, cetaxanib, celutinib, imatinib, dalotinib, imatinib , But not limited to.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with a DNA damaging anticancer agent and / or radiation therapy.

  DNA damage anticancer agents and / or radiation therapy include ionizing radiation, radiation-like drugs, monofunctional alkylating agents (eg, alkyl sulfonates, nitrosoureas, temozolomides), bifunctional alkylating agents (nitrogen mustard, mitomycin C, Cisplatin) antimetabolites (eg 5-fluorouracil, thiopurine, folic acid analogues), topoisomerase inhibitors (eg camptothecin, etoposide, doxorubicin), replication inhibitors (eg aphidicolin, hydroxyurea), cytotoxic agents / cell growth inhibitors Agents, antiproliferative agents, prenyl-protein transferase inhibitors, nitrogen mustards, nitrosoureas, angiogenesis inhibitors, inhibitors of cell proliferation and signaling pathways, apoptosis inducers, interfere with cell cycle checkpoints That drugs, biphosphonates, or any combination thereof, without limitation.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with an inhibitor of inherent multidrug resistance (MDR), particularly an inhibitor of MDR associated with high level expression of a transporter protein. In combination with humans. Examples of such MDR inhibitors include inhibitors of p-glycoprotein (P-gp) such as LY335799, XR9576, OC144-093, R101922, VX853 and PSC833 (Valspodar).

In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with an antiemetic agent to treat nausea or vomiting. Vomiting can result from the use of an HDAC inhibitor (eg, Compound 1) alone, or can result from the use of an HDAC inhibitor (eg, Compound 1) in combination with radiation therapy, acute, delayed, late, and predictive Including vomiting. Antiemetics include neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron), GABA _B receptor agonists (such as baclofen), corticosteroids (US) Dexamethasone, prednisone, prednisolone, or others disclosed in Japanese Patent Nos. 2789118, 2990401, 3048581, 3126375, 3929768, 3996359, 3928326 and 3749712), dopamine Antagonists (domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide, etc.), antihistamines (H1 histamine) Receptor antagonists such as cyclidine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine, etc., cannabis (cannabis, marinor, dronabinol, etc.), and others (trimethobenzamide, ginger, emetrol, propofol, etc.) ).

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with an antiemetic agent selected from among a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with an agent useful for the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoiesis receptor activator (such as epoetin-α).

  In one aspect, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with an agent useful for the treatment of neutropenia. Examples of agents useful for the treatment of neutropenia include, but are not limited to, hematopoietic growth factors that regulate neutrophil production and function such as human granulocyte colony stimulating factor (G-CSF). Not. An example of G-CSF is filgrastim.

  In some embodiments, an HDAC inhibitor (eg, Compound 1) is administered to a human in combination with at least one inhibitor of CYP enzyme. In situations where an HDAC inhibitor is metabolized by one or more CYP enzymes, co-administration with the CYP inhibitor reduces the in vivo metabolism of the HDAC inhibitor and improves the pharmacokinetic properties of the HDAC inhibitor.

  Other combination therapies are disclosed in International Patent Application Publication Nos. 08/082856 and 07/109178, both of which are hereby incorporated by reference in their entirety.

(Radiotherapy)
In one aspect, the HDAC inhibitor (eg, Compound 1) is administered in combination with radiation therapy. Radiation therapy (also called radiation therapy) is the treatment of cancer and other diseases using ionizing radiation. Ionizing radiation deposits energy that damages or destroys cells in the area being treated (the “target tissue”) by damaging genetic material and making these cells unable to continue to grow. Or Radiation damages both cancer cells and normal cells, but the latter can better repair itself and function properly. Radiation therapy can be used to treat localized solid tumors such as cancer of the skin, tongue, larynx, brain, breast, prostate, colon, uterus and / or cervix. It can also be used to treat leukemias and lymphomas (hematopoietic cells and lymphoid cancers, respectively).

  A technique for delivering radiation to cancer cells is to place radioactive implants directly within the tumor or body cavity. This is referred to as internal radiation therapy (brachytherapy, intra-tissue radiation, and intracavitary radiation are types of internal radiation therapy). With internal radiation therapy, the radiation dose is concentrated in a small area and the patient is hospitalized for several days. Internal radiation therapy is frequently used for cancer of the tongue, uterus, prostate, colon, and cervix.

  The term “radiotherapy” or “ionizing radiation” includes all forms of radiation, including but not limited to α, β and γ radiation and ultraviolet radiation. Radiation therapy with or without concurrent or sequential chemotherapy is cancer of the head and neck, breast, skin, anogenital organs, and certain non-malignant such as keloids, desmoid tumors, hemangiomas, arteriovenous malformations and histiocytic X It is an effective method for disease.

  To reduce side effects due to at least one other therapeutic treatment, such as radiation-induced normal tissue fibrosis or chemotherapy-induced tissue necrosis (chemotherapy-induced tissue necrosis). , Methods using HDAC inhibitors (eg, Compound 1) are provided, and the methods provided herein also synergistically inhibit tumor cell growth using radiation therapy and other anti-cancer agents.

(RAD51)
DNA damage causes chromosomal instability, carcinogenesis, cell death, and severe cellular dysfunction. DNA repair systems are very important for live cell survival. The two major DNA repair mechanisms involved in repairing double-stranded DNA breaks are homologous recombination (HR) and non-homologous end joining (NHEJ). The eukaryotic RAD51 gene is an ortholog of E. coli RecA, and the protein of the gene product RAD51 plays a central role in homologous recombination.

  Many therapeutic treatments, such as anticancer drugs, exert a therapeutic effect through their ability to produce DNA damage to cells. If cells, such as cancer cells, have an active DNA repair mechanism, the therapeutic effect of such treatment may be impaired and high doses may be required to achieve the desired therapeutic effect. is there.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is used to reduce cellular DNA repair activity in a human with cancer.

  In one aspect, a method of treating cancer by using an HDAC inhibitor (eg, Compound 1) that reduces cellular DNA repair activity in combination therapy is presented. A method of combination therapy is described in which an HDAC inhibitor (eg, Compound 1) interferes with DNA repair mechanisms involving RAD51 or BRCA1.

  In one aspect, a method for treating a cancer associated with a deficiency in non-homologous end joining of DNA (a) is therapeutically effective in a human having a cancer associated with a deficiency in non-homologous end joining of DNA. Administering an amount of an HDAC inhibitor (eg, Compound 1); and (b) subjecting the human to a treatment capable of damaging cellular DNA.

  Defects in DNA non-homologous end joining include defects in genes selected from the group consisting of Ku70, Ku80, Ku86, Ku, PRKDC, LIG4, XRCC4, DCLRE1C, and XLF. In one aspect, the cancer is selected from Burkitt lymphoma, chronic myeloid leukemia, and B cell lymphoma. In one aspect, the cancer is described herein.

  In one aspect, an HDAC inhibitor (eg, Compound 1) is used for the treatment of telomerase-independent telomere maintenance ATL positive cancer in humans.

  Additional combination therapies, including inhibiting RAD51 activity, treatment strategies, etc. (eg, HDAC inhibitors (eg, Compound 1)) are described in US Patent Publication No. 20080183877 and International Patent Application Publication No. 08/082856 ( Both of which are incorporated herein by reference).

(Kit / Product)
Kits and products are also described herein for use in the treatment methods used as described herein. Such kits include a carrier, package or container that is compartmentalized to receive one or more containers, such as vials, tubes, and the like. Each of the containers includes one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the container is formed from a variety of materials such as glass or plastic.

  The products provided herein include packaging materials. Examples of packaging materials used when packaging pharmaceutical products include US Pat. Nos. 5,323,907, 5,052,558, and 5,032,252. Examples of pharmaceutical packaging materials include blister packs, bottles, tubes, pumps, bags, containers, bottles and any packaging material suitable for the selected formulation and the intended mode of administration and treatment, It is not limited to these. A wide range of formulations of the compounds and compositions provided herein are contemplated.

  Such a kit optionally includes an identification statement or label or instructions regarding its use in the methods described herein.

  In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container if the letters, numbers, or other characters that form the label are attached to the container itself, molded, or etched. A label is associated with a container if the label is present in a container or carrier that also holds the container, for example as a packing insert. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates instructions for use of the contents, as in the methods described herein.

  In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack contains a metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied by a notice associated with the container in a form defined by a governmental authority that regulates the manufacture, use, or sale of the pharmaceutical product. The notice reflects the government's approval for the form of the drug for administration to humans or animals. Such a notice is, for example, an approved label made by the US Food and Drug Administration for a prescription drug, or an approved product insert.

(Example)
The examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

(Synthesis of Compound 1 (HCl))
Compound 1 (HCl) is prepared as outlined in Example 7 of US Pat. No. 7,276,612. The contents of US Pat. No. 7,276,612 are hereby incorporated by reference in their entirety.
(Example 1: IV solution of Compound 1)

  Compound 1 was formulated as an intravenous (IV) solution for the first clinical trial in humans. An IV solution is an aqueous solution formulation intended for infusion administration after dilution with isotonic saline. Each single-use vial contains 25 mL of a 5 mg / mL (0.5%) solution of Compound 1 in isotonic saline, and 50 mM lactate buffer (pH 4.0-4.5). All excipients in clinical formulations are official excipients and are generally used in parenteral formulations. The quantitative composition of the formulation is shown in Table 1. Recommended storage conditions are 2 ° C to 8 ° C.

Example 2. Immediate release capsule
Immediate release capsules are formulated by mixing microcrystalline cellulose, lactose and magnesium stearate with the HCl salt of Compound 1 and then adding the mixture to gelatin capsules (see Table 2). Capsules are produced in two strengths. The 20 mg dose strength contains 20 mg HCl salt of Compound 1 in a size 4 Swedish orange hard gelatin capsule. The 100 mg dose strength contains 100 mg of the HCl salt of Compound 1 in a size 2 dark green hard gelatin capsule. The capsule is packed in a 30 cc HDPE bottle, sealed with an induction seal and capped with a screw cap made safe for children. The 20 mg dose strength is packed with 50 capsules per bottle. A dose strength of 100 mg is packaged with 30 capsules per bottle. Store bottles at a controlled room temperature of 20-25 ° C (68-77 ° F).

(Example 3: sustained release multiparticulate pulse formulation)

  80 g of sodium chloride and 24 g of polyvinylpyrrolidone are dissolved in 1.2 kg of water and 400 g of ground compound 1 (HCl) are suspended therein.

  In a fluid bed coater, 400 g of starch / sugar seed (30/50 mesh) is suspended in warm air until the seed is uniformly coated with the desired medicinal properties, and a compound 1 (HCl) suspension. Spray coat with.

  Magnesium stearate in isopropyl alcohol is mixed with Eudragit NE30D (Rohm Pharma of Weitterstadt, Germany) in the proportion of dried polymer 2 and magnesium stearate 1. By spraying a sufficient amount of polymer suspension onto the active core, a specific film coating thickness is obtained and a specific lag time and release rate is achieved for the population of pellets. The final coated pellet is dried at 50 ° C. for 2 hours to completely and reliably remove moisture and stabilize the core contents.

  The procedure is repeated in at least one or more batches using different coating thicknesses to have different delay times and release rates. In this example, two populations are prepared, one with a 10% weight gain due to coating and the other with a 30% weight gain. A unit dose is prepared by mixing the two populations together in a predetermined ratio and filling the mixture into capsules.

  After oral administration of a unit dose to humans, the first population of pellets does not begin to release Compound 1 (HCl) until an initial lag time of about 2-3 hours has elapsed. The second population of pellets does not begin to release Compound 1 (HCl) until an initial delay time of about 6-7 hours has elapsed. The average release time for each population of pellets (the time when half of the drug was released) should be separated from each other for at least 3-4 hours.

  Fluidized bed coaters are well known in the art, but other coating equipment and methods well known in the art may be used.

Example 4: Sustained release alternative multiparticulate pulse formulation
The active core is prepared as in Example 3. Magnesium stearate and triacetin plasticizer are mixed with the Eudragit RS 30D suspension in a dry weight ratio of 1: 0.6: 2. A polymer suspension is coated onto the core as in Example 3 to prepare multiple populations. Each population has a specific coating thickness and provides a specific lag time and release rate of the drug in the aqueous environment used.

  Different populations of pellets are mixed and the mixture is used to fill capsules as described in Example 3.

(Example 5: Pulse preparation-capsule tablet)
A pulsed release dosage form for administration of Compound 1 (HCl salt) was formulated (1) two individual compressed tablets, each having a different release profile, followed by (2) the 2 One tablet is prepared by encapsulating in a gelatin capsule and closing and sealing the capsule. The components of the two tablets are as follows.

  Prepare tablets by wet granulating individual drug particles and other core ingredients, or by directly compressing a mixture of ingredients, as can be done using a fluid bed granulator. . Tablet 1 is an immediate release dosage form that releases the active agent completely within 1-2 hours after administration.

  Half of the immediate release tablet was laid down with Delayed Coating No. Coat with 1 to obtain tablet 2. Tablet 2 delays the release of Compound 1 (HCl) for approximately 3-5 hours after administration. Half of the immediate release tablet was laid down with Delayed Coating No. Coat 2 to obtain tablet 3. Tablet 3 delays the release of Compound 1 (HCl) about 4-9 hours after administration. Coating is performed using conventional coating techniques such as spray coating.

Oral administration of the capsule to the patient should result in a release profile with two pulses. The initial release of Compound 1 (HCl) occurs about 3-5 hours after administration, and the release of Compound 1 (HCl) from the second tablet occurs about 7-9 hours after administration.
Example 6: Pulsed formulation-capsule or tablet beads

  The method of Example 5 is repeated except that drug-containing beads are used instead of tablets. Immediate release beads are prepared by coating an inert support material such as lactose with the drug. The immediate release beads are coated with a sufficient amount of enteric coating material to provide a period of about 3 to 5 hours of drug release. A second fraction of beads is prepared by coating the immediate release beads with a greater amount of enteric coating material sufficient to provide a period of about 7-9 hours of drug release. Two groups of coated beads are encapsulated as in Example 5 or compressed into a single pulse-release tablet in the presence of buffer.

(Example 7: sustained release tablet)
A sustained release tablet of Compound 1 (HCl) is prepared by first preparing a sustained release excipient. A sustained release excipient is prepared by dry blending the required amount of xanthan gum, locust bean gum, pharmaceutically acceptable hydrophobic polymer and inert diluent for 2 minutes in a high speed mixer / granulator. While moving the chopper / impeller, water was added and the mixture was granulated for an additional 2 minutes. The granules were then dried in a fluid bed dryer until a dry weight loss (“LOD”) of 4-7% was reached. The granules were then milled using a 20 mesh screen. The components of the sustained release excipient are listed in Table 6 below.

  Next, the sustained release excipient prepared as detailed above is dry blended with the desired amount of Compound 1 (HCl) in a V-blender for 10 minutes. For the following examples, an appropriate amount of tableting lubricant Pruv® (sodium stearyl fumarate, NF) is added and the mixture is blended for an additional 5 minutes. This final mixture is compressed into tablets. Each tablet contains 10% by weight of Compound 1 (HCl). The tablets produced weighed 500 mg (diameter 3/8 inch and hardness 2.6 Kp). The proportions of tablets are listed in Table 7 below.

  A dissolution test is then performed on the tablets. The dissolution test is performed in an automated USP dissolution apparatus (Paddle Type II, pH 7.5 buffer, 500 mL, 50 rpm). The tablet should release about 30% of Compound 1 (HCl) in 2 hours, followed by sustained release such that about 98% of Compound 1 (HCl) is released after 12 hours.

Example 8 Coated Sustained Release Tablet
Sustained release excipients were prepared as described above by dry blending the required amounts of xanthan gum, locust bean gum and inert diluent. Two more minutes were spent on granulation after the addition of the ingredients (granulation for a total of 4 minutes after addition). An ethylcellulose aqueous dispersion was used in place of water in the above method. The components of the sustained release excipient are listed in Table 8 below.

  Xanthan gum and locust bean gum are dry blended in a V-blender for 10 minutes, dextrose is added and the mixture is blended for an additional 5 minutes. The aqueous ethyl cellulose dispersion is then added and blended for an additional 5 minutes. The resulting granules are then compressed into tablets with sodium stearyl fumarate as a tableting lubricant. The tablets are then coated with additional ethylcellulose aqueous dispersion. To achieve this, ethylcellulose (Surelease®, 400 g) is mixed with water (100 g) to form an aqueous suspension. The tablets were then applied to a Keith Machinery coated pan (diameter 350 mm; pan speed 20 rpm; spray gun nozzle 0.8 mm; tablet bed temperature 40 ° C. to 50 ° C .; charge 1 kg per batch; dry air—Conair Prostate 1250, 60 Coating within a temperature range from 0 ° C to 70 ° C. Tablets are coated to a weight gain of about 5%. The tablet should weigh about 500 mg. Tablet proportions are listed in Table 9 below.

  Dissolution testing is performed in an automated USP dissolution apparatus in a manner that models the passage through the gastrointestinal tract. Coated tablets must not release more than 10% of compound 1 (HCl) during the first 1-2 hours, after which about 90% -100% of compound 1 (HCl) is released after 12 hours. Thus, compound 1 (HCl) must be released at a stable rate.

Example 9: In vitro release profile
A dissolution profile is obtained using a United States Pharmacopia Apparatus I at 37 ° C. and 100 RPM. The dissolution medium is changed over time, starting with 0.1N HCl for 0-2 hours. For 2-4 hours, the medium was a phosphate buffer at pH 6.5, and for 4-24 hours, the medium was a phosphate buffer at pH 7.5.

  Alternatively, the dissolution profile is performed using a USP Type III (VanKel Bio-Dis II) instrument.

Example 10: In vitro feeding / fasting dissolution protocol
Test formulations are evaluated under various dissolution conditions to determine pH, media, agitation, and equipment effectiveness. Dissolution testing is performed using a USP Type III (VanKel Bio-Dis II) instrument. In vitro dissolution experiments contain 30% peanut oil (“fed”) to determine the difference (if any) in dissolution kinetics between the fed and fasted states of a series of formulations Modeling the gastrointestinal tract with a typical dietary fat load performed in solution. The control determined the dissolution rate in the solution lacking fat intake (“fasted”). The pH-time protocol (modeling the digestion process over the range from acid to alkali) is described in Table 10 below. Agitation is 15 cpm. The sample volume tested is 250 mL.

  Enteric coatings on tablets are expected to provide tablets that provide dissolution rates that do not differ significantly between fasted and fed states.

Example 11: In vitro dose scheduling study
Pharmacokinetic (PK) data from human patients was used to model various dosing regimens using human cell lines: Jurkat (leukemia) and HCT-116 (colon tumor). Human cell lines were treated with or without an HDAC inhibitor (eg, Compound 1). Cells were cultured and treated according to different regimens and concentrations and the corresponding dosing regimen (continuous low dose: 0.2 μM; intravenous (IV): 2 μM for 3 hours + 0.3 μM for 4 hours; oral BID: 0.00). 4 μM 4 hours × 2, 4 hours apart; oral continuous BID: 0.4 μM 8 hours; oral continuous TID: 0.266 μM 12 hours), then mimics human in vivo PK Washed away to do.

  Figures 1 and 2 summarize the results of the in vitro dose scheduling study. It was determined that continuous exposure of the HDAC inhibitor (ie, Compound 1) for at least 8 hours resulted in good efficacy. As with IV administration modeled with 8 hours exposure, oral BID administration is more effective when administered continuously (ie, 4 hours apart) than with intermittent administration. Three times daily oral administration (TID administration) was better than twice daily administration (BID administration), approaching a continuous 0.2 μM level.

After staining with Annexin V-FITC and propidium iodide (PI), cell viability was examined by analyzing apoptosis using a fluorescence activated cell sorter (FACS). Briefly, after treatment, 1 × 10 ⁶ cells were washed with phosphate buffered saline (PBS) and then labeled with Annexin V-FITC / PI in binding buffer according to the manufacturer's protocol. FITC and PI fluorescence signals were detected at 518 nm and 620 nm, respectively, on a Beckman Coulter FACS instrument (Fullerton, CA). Data was analyzed using Flow Jo software (Tree Star, Ashland, OR).

Example 12: Phase 1 study of safety and tolerability of oral capsule form of Compound 1 (HCl) in patients with advanced cancer
This is a phase 1, dose escalation study of safety, pharmacokinetics, and pharmacodynamics of Compound 1 (HCl) administered orally to patients with advanced cancer.

(the purpose)
This study aims to determine the highest dose of Compound 1 (HCl) that can be taken without causing serious side effects in patients with advanced cancer. The study focuses on the safety of the test drug (Compound 1 (HCl)) and whether the treatment schedule is tolerated by the patient.

(Examination design)
In Phase 1 dose escalation trials, up to 7 cohorts were followed by 3 different dosing schedules within a 28-day cycle (5 days of administration followed by 2 days of non-administration, 5 days of administration until the maximum tolerated dose was reached. 9 days non-administration, 7 days administration followed by 7 days non-administration), starting at a dose of 30 mg / m ^{2, with} a dose of up to 90 mg / m ² at approximately 4-6 hour intervals 1 (HCl) is received orally twice or three times daily.

(Eligibility)
Patients should meet the following criteria: at least 18 years of age or older; histologically confirmed measurable solid tumor that has recurred after standard treatment or because there is no standard treatment, non-Hodgkin Lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, or multiple myeloma; ability to swallow oral capsules without difficulty; life expectancy> 12 weeks; ECOG performance status ≤ 2; creatinine ≤ 1.5 x institutional upper reference limit (ULN ); Total bilirubin ≤ 1.5 x institutional ULN (if not elevated from the described Gilbert syndrome); AST and ALT ≤ 2.5 x institutional ULN (in the presence of liver metastases ≤ 5 × institutionalized ULN); platelet count ≧ 100,000 / μL; ANC ≧ 1500 / μL; Hgb ≧ 9.0 g / dL; treated with corticosteroids Not, patients with treated stable asymptomatic brain metastases previously obtain becomes subject; can sign written informed consent voluntarily.

(result)
When delivered using an immediate release capsule formulation, the therapeutic effect of Compound 1 is achieved with 2 or 3 consecutive doses (each dose administered 4-6 hours apart) on the day scheduled for administration. It was. The administration was performed at the same time every day. Over a daily exposure range of 0.63 to 2.15 μM · h, three times daily (TID) continuous administration is a higher average of thrombocytopenia when compared to twice daily (BID) continuous administration. Was associated with a grade. When delivered using an immediate release capsule formulation, the therapeutic effect of Compound 1 was achieved with two doses 4-6 hours apart on the day scheduled for administration. Two doses were given daily at the same time, and a second dose was given approximately 4-6 hours after the first dose.

In patients with solid tumors and lymphomas, the pharmacodynamic response to Compound 1 is grade 4 when the patient receives the drug in a cycle consisting of 7 days of oral administration followed by 7 days of non-administration. Limited incidence of thrombocytopenia (platelet count <25000 / mm ² ) was achieved. If the patient experiences a treatment-related decrease in platelets up to 25000 / mm ² , the severity of thrombocytopenia improves with a cycle consisting of 5 consecutive days of oral administration followed by 9 consecutive days of non-administration. obtain.

The following pharmacokinetic information was determined for patients who received a dose of 30 mg / mm ² of the capsule formulation of Example 2. Cancer patients with solid tumors received the 30 mg / mm ² dose capsule formulation of Example 2. Blood samples collected up to 24 hours after dosing were analyzed for pharmacokinetic evaluation. Plasma was collected by centrifugation and stored at approximately -70 ° C until analysis. The concentration of Compound 1 was determined in plasma using an HPLC gradient system (Hewlett Packard model 1100), using a Sciex API 3000 and a reverse phase column (Phenomenex, Luna C18, 3.0 μm, 50 × 2 mm id). And centrifuged. The mobile phase gradient consisted of 0.2% formic acid (A) in water and 0.2% formic acid (B) in methanol. The flow rate was 0.4 mL / min and the run time was 2.75 minutes. Pharmacokinetic analysis was performed using WinNonlin Professional Edition (Pharsight Corporation, Version 5.2). Nominal sampling times and nominal dose levels were used. The plasma concentration AUC _0-4h of Compound 1 was 0.272 ± 0.051 μM · h (mean ± SE).

The 95% confidence interval for mean AUC _{0-8h at} a dose of 60 mg / mm ² is estimated to be 0.210 to 0.742 μM · h based on a single dose of 30 mg / mm ² immediate release capsule formulation. The once-daily oral controlled release formulation dose-normalized average AUC _0-8 h is calculated to be in the range of _{0.0033 to 0.0124} (μM · h) / (mg / m ² ).

Example 13: Combination therapy: Bortezomib and Compound 1 in in vitro and in vivo models of neuroblastoma
Current treatments for neuroblastoma often fail due to chemotherapy resistance. The current study examined the effects of Compound 1 and the proteasome inhibitor bortezomib in the treatment of neuroblastoma.

Neuroblastoma cell lines and primary neuroblastoma cultures from patients were treated with bortezomib alone, compound 1 alone, or a combination of both drugs for 48 hours. Cells were also treated with the HDAC inhibitors vorinostat, sodium butyrate and valproic acid, and viability was assessed by calcein AM assay. MRNA from treated cells was evaluated at 6 and 24 hours using U133 + mRNA expression array and Ingenuity analysis. Dichlorofluorescein (DCF) was used to measure reactive oxygen species (ROS). Cell viability measurements were repeated in the presence of N-acetylcysteine (NAC). Western blot evaluated caspase-3 and PARP cleavage. Nude mice were injected subcutaneously with 10 ⁷ SMS-KCNR cells and treated with a daily dose of 0.5 mg / kg bortezomib, 12.5 mg / kg of Compound 1, or a combination of the two drugs. Tumors were measured and imaged twice a week.

Neuroblastoma cell lines and patient cells showed sensitivity to bortezomib and compound 1 at _IC 50 <200 nM of _IC 50 <50 nM and compound 1 of bortezomib. The combination of bortezomib and compound 1 was synergistic. Expression analysis showed up-regulation of NOTCH2 and its ligand as well as c-jun. Both NFk-B and MYCN were significantly down-regulated. DCF analysis showed the formation of ROS and viability measurements showed inhibition of caspase-mediated apoptosis in the presence of NAC. The neuroblastoma xenograft mouse model showed a decrease in tumor volume in mice treated with both bortezomib and Compound 1 when compared to the single agent treatment group with significant survival benefit.

  Bortezomib and Compound 1 synergistically inhibit neuroblastoma growth both in vitro and in vivo (FIG. 10). This combination therapy is effective and well tolerated in a mouse model.

(Example 14: Combination therapy of bendamustine and HDAC inhibitor in cancer treatment)
Colon cancer: HCT-116 (colon cancer) solid tumors were treated with an HDAC inhibitor (ie compound 1) or bendamustine, or a combination of compound 1 and bendamustine. Cells were cultured according to different regimens and concentrations, processed to model the corresponding dosing regimen, and then washed away to mimic human in vivo PK. In the case of a combination of bendamustine and an HDAC inhibitor (ie, Compound 1), the cells were first treated with various doses of HDAC inhibitor (ie, Compound 1) for 18 hours, and then with various doses of bendamustine. Treated for 3 days.

As shown in FIG. 3, in the absence of an HDAC inhibitor (ie, Compound 1), administration of bendamustine up to 100 μM resulted in only about 10% non-viable cells.
However, as clearly shown in FIG. 3, the combination of bendamustine and an HDAC inhibitor (ie, Compound 1) is very potent and significantly more effective than the individually administered compounds. As shown in Table 11, the combination has a combination index (CI) of less than 1, indicating a synergistic mechanism of action. Hence, bendamustine and Compound 1 synergistically inhibit colon cancer both in vitro and in vivo.

  Multiple myeloma: Three different multiple myeloma cell lines U266, NCI-H929 and RPMI-8266 were tested for synergistic activity of HDAC inhibitors (ie, Compound 1) and bendamustine. FIG. 4 shows the results for the U266 cell line. The large increase in apoptosis markers for cells treated with the combination of bendamustine and compound 1 indicates that the combination is indeed a potent inhibitor of multiple myeloma. Table 12 shows that the combination has a combination index (CI) of less than 1 and is a synergistic mechanism of action. Bendamustine and Compound 1 synergistically inhibit multiple myeloma both in vitro and in vivo.

  Lymphoma: The effect of combined administration of an HDAC inhibitor (ie Compound 1) and bendamustine was studied in different types of lymphoma. Synergistic activity was observed for the combination of HDAC inhibitor (ie Compound 1) and bendamustine in mantle cell lymphoma and diffuse large cell lymphoma. 5A and 5B of FIG. 5 show an increase in apoptosis markers of lymphoma cells treated with HDAC inhibitor (ie Compound 1) and / or bendamustine. The figure clearly shows that the efficacy was improved by the combination of bendamustine with an HDAC inhibitor (ie Compound 1). Table 13 shows that the combination has a combination index (CI) below 1 indicating a synergistic mechanism of action. Based on FIGS. 5A and 5B and Table 13, it is speculated that bendamustine and Compound 1 synergistically inhibit lymphoma both in vitro and in vivo.

  Pretreatment with HDAC inhibitors provides very good synergy in combination with bendamustine

  H929 multiple myeloma cells were treated with HDAC inhibitors (ie 200 nM Compound 1) or bendamustine (50 μM) for 1 or 3 days. Additional sequences were tested by first adding bendamustine or an HDAC inhibitor and adding the other after 24 hours. The HDAC inhibitor (ie Compound 1) and bendamustine 24 hours later caused the most cell death in this series (FIG. 8).

Example 15: Role of RAD51 in the synergistic function of bendamustine and HDAC inhibitors
The RAD51 gene is associated with a number of major oncogenes including BRCA1, BCRA2 and the tumor suppressor p53. RAD51 activity is regulated by direct protein-protein interaction with p53. RAD51 increased DNA repair activity when p53 was absent or mutated. The net effect of increased RAD51 activity is to effectively repair DNA damage in cancer cells and neutralize radiation and chemotherapy treatment.

As shown in FIG. 3, in the absence of an HDAC inhibitor (ie, Compound 1), administration of bendamustine up to 100 μM resulted in only about 10% non-viable cells.
However, as shown in FIG. 3, the combination of bendamustine and an HDAC inhibitor (ie, Compound 1) is very potent and is significantly more effective than individually administered compounds. As shown in Table 11, the combination shows a synergistic mechanism of action (based on the Chou and Talay method using the Calcusyn (Biosoft, Ferguson, MO) software program), a combination index (CI) below 1 Have Hence, bendamustine and Compound 1 synergistically inhibit colon cancer both in vitro and in vivo.

  6A of FIG. 6 shows the down-regulation of RAD51 by the HDAC inhibitor (ie, compound 1) and by the combination of the HDAC inhibitor (ie, compound 1) and bendamustine. It is hypothesized that the synergistic activity of the combination of an HDAC inhibitor (ie, compound 1) and bendamustine may be due to down-regulation of RAD51 by the HDAC inhibitor (ie, compound 1). RAD51 represents an essential component of homologous recombination (HR), one of two major DNA double-strand break (DSB) repair pathways in cells; it is represented by two of its components Ku70 and DNA-PKcs. Non-homologous end joining (NHEJ), the second pathway represented in, is not affected by these treatments. 6B and 6C in FIG. 6 show that the combination of Compound 1 and bendamustine results in a synergistic increase in caspase cleavage and apoptosis in multiple myeloma cell lines NCI-H929 and U266. As explained above, the synergistic anti-multiple myeloma activity of the bendamustine-compound 1 combination may be due to a decrease in RAD51 levels due to the HDAC inhibitor (ie, compound 1).

  FIG. 9 shows that pretreatment with an HDAC inhibitor (ie, compound 1) suppresses upregulation of RAD51 caused by bendamustine in Jurkat cells, thereby inhibiting DNA damage repair and enhancing the action of bendamustine Indicates that Cells were pretreated with 0.2 μm HDAC inhibitor (ie, Compound 1) for 1 day in advance, and then 20 μm bendamustine was added to the cells for 1 day.

(Example 16: Tumor growth inhibition test using female SCID mice harboring H929 (multiple myeloma) administered with an HDAC inhibitor alone or in combination with bendamustine)
H929 cell line in female SCID mice administered HDAC inhibitors such as Compound 1BID by intraperitoneal route (IP) for 5 consecutive days over 2-3 complete dosing cycles followed by 2 days of non-administration Tumor growth inhibition was evaluated. H929MM cells were inoculated subcutaneously into the right hind flank of mice at a volume of 100 μL / mouse and a density of 1 × 10 ⁷ cells. Four groups of animals (n = 8 / group) consisted of vehicle (BID, IP, 5d / wk), PCI-24781 alone (12 mg / kg BID, IP, 5d / wk), bendamustine alone 5.0 mg / kg (qd , IP, 2d / wk, Tu, Th), or combinations thereof. Body weight and tumor measurements were collected at least twice weekly for all animals. Blood and tumor samples were collected at the end of the study for pharmacodynamic evaluation.

  As shown in FIG. 7, HDAC inhibitor alone and bendamustine alone showed 73% and 79% tumor growth inhibition, respectively, while their combination showed a markedly superior 93% tumor growth inhibition. . The weight loss at the end of the study was <2.2% for the single agent and 8.1% for the combination. Thus, in situations where acceptable toxicity was measured by weight loss, the combination of HDAC inhibitor with bendamustine significantly inhibited H929 multiple myeloma tumor growth compared to single agent alone.

  Example 17: HDAC inhibitor in combination with chloroquine, perifosine, or platinum

  HDAC inhibitors in combination with chloroquine:

  As shown in FIG. 11, the HDAC inhibitors described herein (eg, Compound 1) were found to act synergistically with chloroquine. Chloroquine is an autophagy inhibitor. Thus, it is hypothesized that the combination drives tumor and / or myeloma cells into the apoptotic pathway activated by an HDAC inhibitor (ie, Compound 1).

  HDAC inhibitors in combination with perifosine:

  Perifosine is an AKT pathway inhibitor. As shown in FIG. 12, pretreatment of HCT-116 cells with an HDAC inhibitor (ie, Compound 1) for up to 24 hours, followed by perifosine administration, inhibited perifosine and HDAC in myeloma cell lines and colon tumor cells. It produced a synergistic effect with the agent (ie Compound 1).

  HDAC inhibitor in combination with platinum (ie compound 1):

  The HDAC inhibitors described herein have been shown to inhibit tumor cells synergistically using platinum-containing agents such as cisplatin and carboplatin. Importantly, in platinum-resistant tumor cells, it was demonstrated that HDAC inhibitors effectively inhibited tumors in combination with cisplatin and / or carboplatin. FIG. 13 demonstrates the synergistic inhibition of platinum resistant ovarian tumor cells by the combination of cisplatin and the HDAC inhibitor described herein (ie, Compound 1).

  The examples and embodiments described herein are for illustrative purposes only, and various changes or modifications should be included within the spirit and scope of the appended claims and disclosure. It has been suggested to those skilled in the art. As will be appreciated by those skilled in the art, certain components described in the above examples may be replaced by other functionally equivalent components such as diluents, binders, lubricants, fillers, coating agents, and the like. May be.

Claims (20)

A pharmaceutical composition comprising:
(A) the following compound 1 or a pharmaceutically acceptable salt thereof;
(B) bendamustine, or a pharmaceutically acceptable ester, salt, or solvate thereof; and (c) at least one pharmaceutically acceptable excipient;
A pharmaceutical composition comprising:   The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a controlled-release pharmaceutical composition.   The pharmaceutical composition comprises the active ingredient (i) at a constant rate from about 6 hours to about 10 hours after oral administration to a human, and (ii) from about 6 hours to about 10 hours after oral administration to a human. 3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is completely released in a pulse over a period of about 6 hours to about 10 hours after oral administration to a human with reduced rate or (iii).   The pharmaceutical composition of claim 2, wherein the pharmaceutical composition releases less than about 10% of the active ingredient in the stomach after oral administration to humans.   The pharmaceutical composition according to claim 1, characterized in that it is suitable for separate, sequential and / or simultaneous administration of bendamustine and compound 1.   The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in the form of a solid oral dosage form.   The pharmaceutical composition according to claim 1, wherein Compound 1 is an HDAC inhibitor.   8. The pharmaceutical composition according to claim 7, wherein the HCl salt of compound 1 is an HDAC inhibitor. A product of a combination of bendamustine, or a pharmaceutically acceptable ester, salt, or solvate thereof and an HDAC inhibitor, wherein the HDAC inhibitor is compound 1 below or a pharmaceutically acceptable salt thereof A product that is a combination of salt.
  10. The combined product of claim 9, wherein bendamustine, or a pharmaceutically acceptable ester, salt, or solvate thereof and the HDAC inhibitor are formulated in a unitized dosage form. .   10. The combined product of claim 9, wherein bendamustine, or a pharmaceutically acceptable ester, salt, or solvate thereof, and the HDAC inhibitor are formulated in separate dosage forms.   10. The combined product of claim 9, wherein the HDAC inhibitor is the HCl salt of Compound 1. Bendamustine, or a pharmaceutically acceptable ester, salt, or solvate thereof for the manufacture of a medicament for the treatment of cancer in a patient in need thereof; and the following compound 1 or a pharmaceutically acceptable salt thereof: Use of combinations.
  Use according to claim 13, characterized in that the cancer is a carcinoma, tumor, neoplasm, lymphoma, melanoma, glioma, sarcoma, and blastoma.   Use according to claim 13, characterized in that the cancer is mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, colon cancer or non-Hodgkin's lymphoma. 14. Use according to claim 13, characterized in that bendamustine and compound 1 or a pharmaceutically acceptable salt thereof are administered simultaneously. 14. Use according to claim 13, characterized in that bendamustine and compound 1 or a pharmaceutically acceptable salt thereof are administered sequentially and bendamustine is administered first. 14. Use according to claim 13, characterized in that bendamustine and compound 1 or a pharmaceutically acceptable salt thereof are administered sequentially and the HDAC inhibitor is administered first. 14. Use according to claim 13, characterized in that the administration of bendamustine and compound 1 or a pharmaceutically acceptable salt thereof is staggered. 14. Use according to claim 13, characterized in that compound 1 or a pharmaceutically acceptable salt thereof is the HCl salt of compound 1.